Section 12

Section Editor: Shyam Sundar Infectious Disease

155. Anti-malarial Drug Resistance 169. Growing Threat of Klebsiella—How to Counter? Neha Agrawal, Anup Singh, Shyam Sundar Aditya Prakash Misra 156. Controversy in 170. with Acinetobacter— Anil Manchanda, Ruchika Manchanda, Veronica Manchanda A Challenge for the Physician 157. in Critically ILL Patients Krishna Padarabinda Tripathy Nitin Sinha 171. Scrub Typhus—Clinical Manifestations 158. Current Controversies in Sepsis Management and Management Atul Bhasin, RK Singal Sudhir Kumar, Govind Kumar, Arshad Ahmad, Amit Kumar Mishra 159. Viral Hemorrhagic Fever: Indian Perspective 172. Burkholderia Species Ghan Shyam Pangtey, Chinmaya Murthy KR, Paramjeet Singh Shubhransu Patro 160. Antimicrobial Stewardship in Clinical Practice— 173. Managing Dermatophytosis (Tinea Infections) in Role of Biomarkers Today’s Scenario Anupam Dey Basavana Gowdappa Hathur, Garehatty Rudrappa Kanthraj 161. Misutilizing Medicine for Biological Warfare 174. Rickettsial Infection Jayanta Kumar Panda, Biswojit Behera Vasantha Kamath, Shreyashi Ganguly, P Siva Karthik Reddy 162. Antimicrobial Resistance: Is It Worrisome? 175. Adult Vaccination Ritu Karoli Nirupam Prakash, Hemant Mittra, Jeevan Prakash 163. Arthropathy 176. Neurocysticercosis—Clinician Recap Liyakat Ali Gauri, Somya Goyal, Asim Khan, Nadeem Liyakat, Qadir Fatima Alok Gupta, Deepak Kumar 164. Atypical Manifestations of Dengue 177. Rabies: A Comprehensive Overview Ashok Kumar, Shubha Laxmi Margekar, Shashi Sinha, Naresh Kumar Purnima Margekar, Urvashi Khan 178. Biomarkers for Diagnosis and 165. Cholera and Plague—Is the Threat Over? Prognosis of Severe Malaria Shyam Chand Chaudhary, Chitranshu Pancholi, Manoj Kumar Mohapatra Kamal Kumar Sawlani, Deepali Mohanty 179. How Fatal Is Plasmodium vivax—To Be Understood 166. Cryptococcal Disease: A Review and Its Management VK Sashindran, Rajneesh Thakur Smita Gupta, Neeraj Kapoor, Ankit Grover 167. Enteric Fever—Challenges to Overcome 180. Emerging and Re-emerging Infectious Diseases in Rupali Malik, Anupam Prakash India—This Millennium 168. and Brucellosis—Can These Be Partha S Karmakar Difficult to Diagnose? Saurabh Srivastava, Amit Gupta, Indal Chauhan

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155 Anti-malarial Drug Resistance

Neha Agrawal, Anup Singh, Shyam Sundar

Abstract Anti-malarial drug resistance is a major public health problem which hinders the control of malaria. In India, resistance of Plasmodium falciparum (Pf) to chloroquine, the cheapest and the most used drug was first reported in the year 1973. Resistance to commonly used antimalarial drugs like choloquine (CQ), mefloquine (MQ), sulfadoxine/pyrimethamine (SP) have been reported across the country. Emergence of artemisinin resistance in P. falciparum strains from Combodia and neighboring countries is a major setback to the antimalarial program of these countries and an ominous sign. Various drug-resistant genetic markers identified for P. falciparum and P. vivax antimalarial drugs, like Plasmodium falciparum Multidrug Resistance Protein 1 (PfMDR1), Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT), The K76T mutation in PfCRT protein is a potent molecular marker of CQ resistance and susceptibility. Antimalarial drug susceptibility and resistance to quinine, amodiaquine (AQ), piperaquine, and lumefantrine is affected by variation in the PfCRT protein mutation. Mutation in C-terminal region of K13 protein is associated with the artemisinin resistance. Detection of drug-resistant parasites in P. vivax malaria is also prevalent worldwide. Prolonged courses of artemisinin-based combination therapies for 6 days are currently efficacious in areas where standard 3-day treatments are failing.

Introduction recommends the use of ACT as first-line of treatment for P. falciparum since 2010 as resistance to commonly used Malaria is a major cause of morbidity and mortality antimalarial drugs like chloroquine (CQ), Mefloquine in the tropical countries. Malaria cases in India have (MQ), sulfadoxine/pyrimethamine (SP) has been reported reduced from 2 million annually in the 1990s to 1 million across the country.2,3 in 2012, with a declining trend since 2002. However, the Plasmodium falciparum (Pf) cases reported has increased to 50.01% in 2012 from 39% in 1995.1 Notably, antimalarial Tools for Monitoring drug resistance is becoming a major public health Drug sensitivity status in India was being assessed problem throughout the globe. In India, chloroquine- following conventional WHO in-vivo protocol till 2002. resistance in P. falciparum was first reported in 1973 This is changed in 2003 since when WHO protocol from Assam. The National Vector Borne Disease Control on “Therapeutic efficacy of antimalarial drugs in Programme (NVBDCP) has been monitoring the response uncomplicated P. falciparum malaria” is being used. The of antimalarial drugs in P. falciparum malaria since criteria classify response in three categories: 1978 throughout India. This helps in formulation of „„ Adequate Clinical and Parasitological Response National Drug Policy and recommends necessary changes (ACPR), in the control strategy including treatment policy to „„ Early Treatment Failure (ETF), and 1 1 contain resistant P. falciparum foci. National Drug Policy „„ Late Treatment Failure (LTF).

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Criteria for Change of Drug Policy K76T mutation located in the first transmembrane domain of PfCRT protein, allows the efflux of diprotonated The treatment drug policy is changed for the area/ chloroquine out of the digestive vacuole by active Block PHC, which reports ≥10% total treatment failure transport.12 Other mutations cause resistance only in (ETF+LTF) to the tested drug, that is, the currently used association with K76T mutation and include C72S, M74I, antimalarials in a sample of minimum 30 P. falciparum N75E, A220S, Q271E, N326S, I356T, and R371I.12 test cases. To reduce emergence of drug resistance, the Antimalarial drug susceptibility and resistance National Drug Policy on Malaria recommends use of to quinine, amodiaquine (AQ), piperaquine, and combination therapy in chloroquine-resistant areas, that lumefantrine is affected by variation in the PfCRT protein is, Artesunate plus Sulfadoxine-Pyrimethamine (AS+SP) mutation.13-16 There is cross-resistance of chloroquine for treatment of P. falcipuram cases.1 with AQ and quinine mainly mediated by 76T, and lumefantrine has an inverse cross-resistance having Genetic Markers of Drug Resistance reduced susceptibility in association with wild-type K76.17 The various drug-resistant markers identified for P. falciparum and P. vivax antimalarial drugs are discussed Plasmodium falciparum Multidrug Resistance- here. Associated Protein (PfMRP) PfMRP is a transmembrane protein produced by PfMRP Plasmodium falciparum Multidrug Resistance gene located on chromosome 1. This multidrug resistance- Protein 1 (PfMDR1) associated protein aids the parasite in transporting out The PfMDR1 gene located on chromosome 5, encodes of drug and organic anionic substrates like oxidized for P-glycoprotein homolog 1 protein,4,5 which belongs to glucuronate, glutathione, etc. from its inside, thus effecting the ATP-binding cassette (ABC) superfamily. Resistance resistance.18,19 to antimalarials is believed to be due to polymorphism, Chloroquine and quinine resistance are associated amplification, or variation in mRNA expression level of the with two mutations in PfMRP at position Y191H and PfMDR1 gene.5 A437S. High sensitivity to various antimalarial drugs such Drug susceptibility to chloroquine, quinine, as chloroquine, quinine, primaquine, piperaquine, and mefloquine, halofantrine, lumefantrine, and artemisinin artemisinin can be demonstrated by genetic knocking are affected by mutations in Pfmdr1 gene at the following out of PfMRP gene in the resistant parasite, and more positions (N86Y, Y184F, S1034C, N1042D, and D1246Y). accumulation of chloroquine and quinine is observed in Amodiaquin resistance is associated with PfMDR1 the sensitive parasite. Thus, PfMRP is not only involved in mutations at N86Y and N1042D position. Chloroquine determining the drug resistance but has role in varying the resistance is associated with K76T and A220S mutation antimalarial response to resistance.19 in the Pf chloroquine resistance transporter (PfCRT) gene and N86Y mutation in the PfMDR1 gene.6-10 Plasmodium falciparum Sodium Hydrogen Exchanger (PfNHE) Plasmodium falciparum Chloroquine Resistance This gene on chromosome 13 codes for a protein associated Transporter with quinine resistance in Pf, and is involved in active As discussed, PfCRT gene mutation has potential role efflux of protons in the parasite to maintain pH at 7.4, in chloroquine resistance. This gene is localized to in response to acidification by anaerobic glycolysis, the chromosome 7 and PfCRT protein belongs to the drug/ primary energy source for the parasite.20 Polymorphism metabolite transporter superfamily and chloroquine in the microsatellite ms470 region exhibited a decrease resistance transporter-like transporter family with ten in quinine susceptibility with an increase in DNNND putative transmembrane domains spanning the digestive repeat motif, whereas increase in quinine susceptibility vacuole membrane of the parasite. is observed with a rise in NHNDNHNNDDD motif. Three The K76T mutation in PfCRT protein is a potent mutations at 790, 894, and 950 codons and polymorphism molecular marker of CQ resistance and susceptibility.11 in the microsatellite region (msR1 and ms3580) showed

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no association with quinine resistance.21 Thus, repeat of the parasite. It catalyses the transfer of electrons polymorphism in PfNHE gene may be used as a valid across the inner mitochondrial membrane to maintain genetic marker to determine quinine resistance in some the electrochemical potential of the membrane. The regions. antimalarial drug atovaquone disrupts the electrochemical potential by binding to the ubiquinol binding site of cytb, Plasmodium falciparum Bifunctional and hence is lethal for the parasite. Mutation at the Dihydrofolate Reductase-Thymidylate Synthase ubiquinol binding site confers atovaquone resistance.26,27 (PfDHFR-TS) Single mutation at Y268N/S/C codon in the cytb gene leads to resistance to atovaquone in P. falciparum field The PfDHFR-TS gene has one exon located on chromosome isolates. 4 encoding for PfDHFR protein and is a bifunctional enzyme involved in two main folate metabolic activities— biosynthesis of dTMP by thymidylate synthase activity Kelch and the reduction of dihydrofolate to tetrahydrofolate Kelch-13 (K13) protein has one exon located on by dihydrofolate reductase (DHFR) activity. The folate chromosome 13. Mutation in C-terminal region of K13 mechanism of PfDHFR-TS enzyme is inhibited by the protein in this region is associated with artemisinin action of antifolate drugs such as pyrimethamine and resistance in both clinical and field isolates by disrupting cycloguanil, thus reducing the production of pyrimidine the domain scaffold. However, the exact function of K13 for DNA replication.22 protein, and the effect of various mutations on the protein Pyrimethamine resistance is mainly associated with will only be known after several studies are conducted to point mutation in the PfDHFR protein at S108D codon, ascertain its nature completely. and further mutation at N51I, C59N, and I164L positions Nonsynonymous polymorphism at Y493H, R539T, strengthens the resistance besides amplification of I543T, and C580Y positions observed in the kelch repeat gene.23,24 region of K13 propeller domain is associated with higher artemisinin resistance. Mutations at codons F446I, Plasmodium falciparum Dihydropteroate Synthase Y493H, P574L, R539T, and C580Y confer a higher degree (PfDHPS) of resistance to artemisinin, and the frequency of C580Y allele mutation is higher and takes longer time for parasite The PfDHPS gene is located on chromosome 8 and encodes clearance when compared to variation in other sites. for PfDHPS protein. PfDHPS synthesizes dihydrofolate, Therefore, K13 propeller protein polymorphism can serve a folate precursor that is essential for the synthesis of as a potent molecular marker indicating emergence and pyrimidine in the parasite by catalyzing the reaction of 28 spread of artemisinin-resistant P. falciparum. pterin derivative and p-aminobenzoic acid (PABA).25 This catalytic enzyme action to synthesize dihydrofolate is Drug Resistance in Vivax Malaria inhibited by sulfa drugs (sulfadoxine and dapsone), which act as an analog to PABA.25 Drug-resistant Plasmodium vivax malaria is also prevalent Resistance to sulfadoxine in P. falciparum is due to worldwide. Its treatment primarily consists of two drugs: S436A/F, A437G, L540E, A581G, and A613T/S mutations Chloroquine (blood schizonticide) targeting the asexual in the PfDHPS protein.24 Sulfadoxine is always provided blood stages of the parasite, and Primaquine (tissue in combination with pyrimethamine (SP) as monotherapy schizonticide), which targets the dormant live stage is associated with antimalarial drug resistance. Point (hypnozoites) of the parasite, responsible for relapse. mutation in both PfDHFR and PfDHPS gene is associated P. vivax is also associated with molecular markers of with resistance to SP.23 drug-resistance, like P. falciparum. Increased susceptibility to chloroquine in P. vivax is strongly associated with the Cytochrome B Y976F mutation in PvMDR1 gene, which is a homolog of PfMDR1. However, the PfCRT gene homolog in P. vivax, Cytochrome b (Cytb) gene is a subunit of cytochrome that is, the PvCRT gene, is not associated with chloroquine- bc1 complex present in mitochondrial inner membrane resistance (unlike in P. falciparum). Mefloquine resistance

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in P. vivax is associated with amplification of PvMDR1 . 7 Sisowath C, Strömberg J, Mårtensson A, et al. In vivo selection of gene. Mutation at Y976F position of PvMRD1 in vitro has Plasmodium falciparum pfmdr1 86N coding alleles by artemether- been shown to be associated with resistance to mefloquine lumefantrine (Coartem). J Infect Dis. 2005;191(6):1014-7. 29,30 . 8 Pickard AL, Wongsrichanalai C, Purfield A, et al. Resistance to and artesunate, in addition to chloroquine. antimalarials in Southeast Asia and genetic polymorphisms in Point mutations at F57L/I, S58R, T61M, and S117T/N pfmdr1. Antimicrob Agents Chemother. 2003;47(8):2418-23. codons of PvDHFR gene are linked to pyrimethamine 9. Sá JM, Twu O, Hayton K, et al. Geographic patterns of Plasmodium resistance and consequently treatment failure with falciparum drug resistance distinguished by differential responses pyrimethamine in P. vivax. The wild type residue V585 in to amodiaquine and chloroquine. Proc Natl Acad Sci U S A. 2009;106(45):18883-9. PvDHPS gene has shown innate resistance to sulfadoxine 10. Sidhu AB, Uhlemann AC, Valderramos SG, et al. Decreasing pfmdr1 and is enhanced by the mutation in A383G and A553G copy number in Plasmodium falciparum malaria heightens codons in PvDHPS, which is similar to PfDHPS mutation susceptibility to mefloquine, lumefantrine, halofantrine, quinine, at codons A347G and A581G.31,32 and artemisinin. J Infect Dis. 2006;194(4):528-35. 11. Fidock DA, Nomura T, Talley AK, et al. Mutations in the P. falciparum digestive vacuole transmembrane protein Pf CRT and evidence for Conclusion their role in chloroquine resistance. Mol Cell. 2000;6(4):861-71. 12. Martin RE, Kirk K. The malaria parasite’s chloroquine resistance Antimalarial drug resistance poses a major hurdle to our transporter is a member of the drug/metabolite transporter victory over the malarial parasite and contributes to failure in superfamily. Mol Biol Evol. 2004;21(10):1938-49. treatment of malaria. Combination therapies targeting different 13. Menard D, Yapou F, Manirakiza A, et al. Polymorphisms in pfcrt, mechanisms of action can delay the emergence and spread of pfmdr1, dhfr genes and in vitro responses to antimalarials in drug-resistant parasites. Molecular markers of drug resistance Plasmodium falciparum isolates from Bangui, Central African play a vital role in the detection of resistance in clinical and Republic. Am J Trop Med Hyg. 2006;75(3):381-7. field isolates when compared to the in vivo efficacy studies and 14. Echeverry DF, Holmgren G, Murillo C, et al. Short report: in vitro tests. Thus, earlier clinical isolates will aid in employing polymorphisms in the pfcrt and pfmdr1 genes of Plasmodium immediate and appropriate treatment that in turn reduces falciparum and in vitro susceptibility to amodiaquine and treatment failure and thereby mortality, and also prevents desethylamodiaquine. Am J Trop Med Hyg. 2007;77(6):1034-8. the spread of resistance. Hence, continuous monitoring and 15. Muangnoicharoen S, Johnson DJ, Looareesuwan S, et al. Role of known molecular markers of resistance in the antimalarial potency surveillance of drug-resistant molecular markers in malaria of piperaquine and dihydroartemisinin in vitro. Antimicrob Agents endemic regions is important in determining and assisting an Chemother. 2009;53(4):1362-6. effective national drug policy for malaria treatment. Therefore, 16. Sisowath C, Petersen I, Veiga MI, et al. In vivo selection of more research is necessary to find new antimalarial drugs/ Plasmodium falciparum parasites carrying the chloroquine- for multidrug resistance parasites. susceptible pfcrt K76 allele after treatment with artemether- lumefantrine in Africa. J Infect Dis. 2009;199(5):750-7. 17. Petersen I, Eastman R, Lanzer M, et al. Drug-resistant malaria: References molecular mechanisms and implications for public health. FEBS Lett. 2011;585(11):1551-62. . 1 National Vector Borne Disease Control Programme, Delhi, 2020. 18. Klokouzas A, Tiffert T, van Schalkwyk D, et al. Plasmodium Available from http://www.nvbdcp.gov.in/ falciparum expresses a multidrug resistance-associated protein. 2. Government of India. National Drug Policy on Malaria, New Delhi: Biochem Biophys Res Commun. 2004;321(1):197-201. Directorate of National Vector Borne Disease Control Programme; 19. Raj DK, Mu J, Jiang H, et al. Disruption of a Plasmodium falciparum 2013. multidrug resistance-associated protein (PfMRP) alters its fitness . 3 Parija SC, Praharaj I. Drug resistance in malaria. Indian J Med and transport of antimalarial drugs and glutathione. J Biol Chem. Microbiol. 2011;29(3):243-8. 2009;284(12):7687-96. . 4 Foote SJ, Thompson JK, Cowman AF, et al. Amplification of the 20. Bosia A, Ghigo D, Turrini F, et al. Kinetic characterization of Na+/ multidrug resistance gene in some chloroquine-resistant isolates H+ antiport of Plasmodium falciparum membrane. J Cell Physiol. of P. falciparum. Cell. 1989;57(6):921-30. 1993;154(3):527-34. 5. Durai Singh MT, Cowman AF. Contribution of the pfmdr1 gene to 21. Briolant S, Pelleau S, Bogreau H, et al. In vitro susceptibility to antimalarial drug-resistance. Acta Trop. 2005;94(3):181-90. quinine and microsatellite variations of the Plasmodium falciparum . 6 Sidhu AB, Valderramos SG, Fidock DA, et al. pfmdr1 mutations Na+/H+ exchanger (Pfnhe-1) gene: the absence of association in contribute to quinine resistance and enhance mefloquine and clinical isolates from the Republic of Congo. Malar J. 2011;10:37. artemisinin sensitivity in Plasmodium falciparum. Mol Microbiol. 22. Thaithong S, Ranford-Cartwright LC, Siripoon N, et al. Plasmodium 2005;57(4):913-26. falciparum: gene mutations and amplification of dihydrofolate

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reductase genes in parasites grown in vitro in presence of 28. Ariey F, Witkowski B, Amaratunga C, et al. A molecular marker pyrimethamine. Exp Parasitol. 2001;98(2):59-70. of artemisinin-resistant Plasmodium falciparum malaria. Nature. 23. Urdaneta L, Plowe C, Goldman I, et al. Point mutations in 2014;505(7481):50-5. dihydrofolate reductase and dihydropteroate synthase genes of 29. Suwanarusk R, Russell B, Chavchich M, et al. Chloroquine resistant Plasmodium falciparum isolates from Venezuela. Am J Trop Med Plasmodium vivax: in vitro characterization and association with Hyg. 1999;61(3):457-62. molecular polymorphisms. PLoS One. 2007;2(10):1089. 24. Wernsdorfer WH, Noedl H. Molecular markers for drug resistance in 30. Imwong M, Pukrittayakamee S, Pongtavornpinyo W, et al. Gene malaria: use in treatment, diagnosis and . Curr Opin amplification of the multidrug resistance 1 gene of Plasmodium Infect Dis. 2003;16(6):553-8. vivax isolates from Thailand, Laos, and Myanmar. Antimicrob 25. Foote SJ, Cowman AF. The mode of action and the mechanism of Agents Chemother. 2008;52(7):2657-9. resistance to antimalarial drugs. Acta Trop. 1994;56(2-3):157-71. 31. de Pécoulas PE, Tahar R, Ouatas T, et al. Sequence variations in the 26. Barton V, Fisher N, Biagini GA, et al. Inhibiting Plasmodium Plasmodium vivax dihydrofolate reductase-thymidylate synthase cytochrome bc1: a complex issue. Curr Opin Chem Biol. gene and their relationship with pyrimethamine resistance. Mol 2010;14(4):440-6. Biochem Parasitol. 1998;92(2):265-73. 27. Gil JP, Nogueira F, Strömberg-Nörklit J, et al. Detection of 32. Marfurt J, de Monbrison F, Brega S, et al. Molecular markers atovaquone and malarone resistance conferring mutations in of in vivo Plasmodium vivax resistance to amodiaquine plus Plasmodium falciparum cytochrome b gene (cytb). Mol Cell Probes. sulfadoxine-pyrimethamine: Mutations in pvdhfr and pvmdr1. J 2003;17(2-3):85-9. Infect Dis. 2008;198(3):409-17.

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156 Controversy in Vaccination

Anil Manchanda, Ruchika Manchanda, Veronica Manchanda

Abstract Ever since the advent of vaccination against communicable diseases there has been concern in the mind of certain people about its adverse outcome. While there is no doubt about efficacy of the time-tested vaccines which have been able to either eradicate or minimize many dangerous communicable diseases but the apprehension remains there, which were not unfounded. There was apprehension of increased incidences of Autism (MMR ), GBS (DPT, ) which later on proved wrong. Dengvaxia saga (2015 with Dengue vaccination), Cutter polio incident (1955), and currently Covid vaccine related adverse effects are few examples which were highlighted out of proportion despite their numbers were few and statistically insignificant. In this article we highlight the various aspects of various controversies revolving around the and their scientific explanations which would help us to overcome these apprehensions for future vaccination strategies.

Introduction and vested interests. However, this fear was not without reasons. Following is the historical facts of Ever since had introduced the first vaccine various concerns against the vaccinations. in 1796, the global use of vaccines has been detrimental in reducing or eradicated the incidence and spread of The Cutter Incident:4 In 1955 Cutter Laboratories produced childhood diseases.1,2 Despite the fact that there are a lot 120,000 polio vaccines (in which the process of inactivating of evidences behind the benefits of vaccines, to provide the live virus proved to be defective), which caused 40,000 against diseases, there has been opposition cases of polio, 53 cases of paralysis, and 5 deaths. This in in certain quarter against the use of vaccines.3 Some of turn also infected the family members of the recipients these biased views are based on perception of personal, leading to additional 113 cases of paralytic polio and religious, or cultural beliefs that vaccines can be more another 5 deaths. It has been rightly described as the worst harmful than good in people who receive them. The Pharmaceutical incident. Controversy of vaccination is about: Other historical facts are given below which created „„ Safety doubts and suspicion in the mind of people regarding „„ Efficacy efficacy and side effects of vaccinations (Table 1). „„ Dosing Despite all the rebuffs to the Antivax (Anti-vaccination) „„ Availability of different vaccines for different region. lobby the concerns raised were not without reasons due This can be attributed to lack of awareness, political to the emergence of certain adverse effects in the ensuing

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TABLE 1 History of controversies in vaccination and evidences for and against them5

Issue Allegation Evidence

MMR vaccine and MMR vaccine can cause zz Initial report suggesting an association between vaccination and autism was autism6 autism drawn back zz Autism usually occurs in early age group than before recommended age of MMR vaccination (12 months) and is genetically determined zz In studies conducted by the epidemiologists there is no increased risk of autism associated with MMR vaccine

DPT Neurological conditions zz Commission on Vaccination and (JCVI) confirmed that the risks following immunization7,8 or neurological problems due to DPT were quite low zz With universal childhood immunization, the number of reported cases fell by >95%, and mortality rates decreased even more dramatically9

Thimerosal10 Increases risk of autism and zz Ethyl mercury (an active ingredient of thimerosal) does not accumulate in the other neurodevelopmental body to harmful levels with consecutive vaccinations disabilities may be increased zz Even after removal of thimerosal from childhood vaccines, incidence of autism by Thimerosal continued to increase zz Studies have not found an increased risk of autism or other neurodevelopmental disabilities associated with thimerosal-containing vaccines in epidemiological studies11 Influenza vaccines may GBS (1978) It is observed that risk of GBS is greater following natural influenza infection than cause GBS12 possible vaccination

Meningococcal vaccine GBS (2005–2008) A large study proved there was no link between Menactra and GBS and can cause GBS12

Autoimmunity13 Vaccines may be responsible There is no established mechanism to explain how vaccinations cause for chronic diseases of autoimmune disease and epidemiologic studies have failed to supported the autoimmune etiology hypothesis that vaccines cause autoimmune diseases

HPV vaccine: Safety Risk of autoimmune zz Several large studies have not established increased risks of autoimmune or and other disorders may neurologic diseases be increased with HPV zz Other studies failed to establish increased risks of POI, POTS, or CRPS vaccination

Aluminum Autoimmune diseases and zz The serum levels of aluminum are well below the toxic range due to aluminum a variety of other disorders, containing vaccines including Macrophagic zz There is hardly any correlation between infant blood or hair aluminum Myofasciitis can be concentrations and vaccine history attributed to aluminum in zz There were lower incidence of autoimmune disease with higher quantities of vaccines14 injected aluminum adjuvants zz Systemic symptoms of MMF secondary to aluminum salts at injection sites have never been established15

Too many too soon Too many vaccines given zz Infants can handle as many as 10,000 vaccines at one time early in life might interfere zz Long-lasting, gross alterations of the immune system has been found with with the immune system childhood vaccinations zz The number of vaccines or vaccine antigens received in early childhood did not increase risk of disease or developmental delay as per many epidemiological studies Hepatitis vaccine 199826 Multiple sclerosis The IOM committee concluded that there is no link between MS and hepatitis B vaccination CRPS, complex regional pain syndrome; GBS, Guillain-Barré syndrome; HPV, human papillomavirus; IOM, Institute of Medicine; MMR, measles, mumps, and rubella; POI, primary ovarian insufficiency; POTS, postural orthostatic tachycardia syndrome

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years. To highlight these concerns, few following events Current recommendations of : Despite throw insight into the safety and concerns about the these shortcomings, dengvaxia has been approved by FDA vaccination. for use in the following conditions— „„ Children 9–16 years old in endemic areas Dengue Vaccine Controversy16,17 „„ Laboratory confirmed previous infection About 400 million people are infected with Dengue every Controversies Surrounding HPV Vaccination year, out of which almost 25000 people die of dengue The controversy surrounding HPV Vaccine is about its— hemorrhagic fever (DHF). Due to lack of cure for Dengue „„ Safety concerns and high mortality rate in the countries with less advanced „„ Dose scheduling medical system, scientists have since long been on a quest „„ Two strains/four strains vaccine to develop a vaccine. Recently, Dengvaxia (Vaccine against „„ Whether males should be vaccinated Dengue) was approved by Food and Drug Administration „„ Till what age one should be vaccinated (FDA) to prevent dengue. Despite the fact that this vaccine has the capability to save millions of lives , its approval was Safety concerns: The main adverse reactions reported not without controversy. with HPV vaccination were: headaches (70%), general Philippines in 2015 launched a massive campaign to fatigue (53%), coldness of the legs (53%), limb pain (50%), immunize children against the dreaded disease. After limb weakness (48%), difficulty in getting up (48%), about 1 million children were vaccinated, the controversy fainting (43%), decreased capability to learn (43%), was raised as the vaccine was associated with the deaths arthralgia (43%), tremulousness (40%), gait disturbances of three children in the Philippines. However, before (40%), disturbed menstruation (35%), and dizziness addressing this issue it is imperative, we understand how (30%). Besides this, it was associated with enhance the immune system reacts to dengue virus. There are two autoimmune response and CNS side effects including types of antibodies generated against any pathogen— syncope. Possibility of presence of the active aluminum 19 neutralizing and non-neutralizing. The dengue virus adjuvant might be contributing to these side effects. has four serotypes and the antibodies generated against In India, with regards to HPV vaccine, Program for 20 one serotype while it may react with another serotype as Appropriate Technology in Health (PATH), a nonprofit well, it does not always neutralize the antigen. This may based in Seattle, in 2009 launched a $3.6 million HPV be acceptable for other pathogens since the antibody- trial, funded by the Bill & Melinda Gates Foundation, in pathogen complex reach the macrophage and is eventually 24,777 adolescent girls in Andhra Pradesh and Gujarat destroyed. However, dengue virus is unique as it primarily states; however, it was prematurely terminated by the infects the macrophage. Thus, antibodies that have government when news outlets reported the death of developed against one variant of dengue can make seven girls. However, on further analysis it was found that subsequent infections far more lethal. The preexisting non five of those deaths were evidently unrelated to the vaccine neutralizing antibodies bind to dengue virus antigen and itself. The causes attributed to their death were drowning attract macrophages facilitating spread. In this manner (1 girl), snake bite (1 girl), suicide (2 girls), malaria (1 girl). the non-neutralizing antibodies allow the virus to infect The other two deaths were still uncertain. multiple cells with ease, thus causing the severity of Dosing of vaccine and cost: Another dilemma with respect the second infection with respect to the first one. This to the HPV vaccine is the dosing schedule.21 While one phenomenon is referred as antibody enhancement.18 dose by itself is quite immunogenic so as to provide lasting Now, though dengvaxia was indeed engineered to protection from HPV 16 and 18, data regarding long- protect against all four serotypes of dengue, many people term protection after 7 years and protection from HPV did not develop neutralizing antibodies against all the and cervical precancerous lesions is lacking. Conversely serotypes. In this unfortunate people, the vaccine acted as the immunogenicity produced by two-dose and three- a primary infection thus making the second infection far dose HPV vaccine schedules, measured using antibody more lethal (Fig. 1). responses in young females, is comparable.21

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Fig. 1: Neutralizing and non-neutralizing antibodies in dengue infection

Current Recommendations Adults ages 27 through 45 years: Despite the facts that Children and adults ages 9 through 26 years: HPV HPV vaccine is approved by FDA to be given through age vaccination is routinely recommended at age 11 or 12 45 years, HPV vaccination is not recommended for all years; although it can be started as early as age 9 years. adults ages 27 through 45 years as effect of vaccination HPV vaccination is recommended for all women before starts to diminish by age 18. Therefore, its benefit for attaining 26 years of age who were not adequately cancer prevention is doubtful as people get older. The vaccinated earlier. Children below 15 years require only ACS (American Cancer society) does not recommend two doses to be fully protected. People who start the series HPV vaccination for persons older than age 26 years.22 at age 15 or older and people with weakened immune Instead, ACIP23 recommends that because more people system need three doses to be fully protected. have already been exposed to the virus. HPV vaccination

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in this age range provides less benefit; clinicians consider circulating viruses and vaccine viruses correspond to discussing with their patients in this age group about the each other. Even when they do correspond, efficacy of benefits of the vaccination. vaccine is not beyond 40–60%. But, if the vaccine virus as recommended by WHO is different from the locally Male HPV vaccination: The US Advisory Committee on 23,24 circulating virus, it may be partially effective or not Immunization Practices (ACIP) licensed HPV4 for boys and young men in 2009. HPV vaccine in males can effective at all. Hence, vaccines are not foolproof method help prevent genital warts as well as a variety of cancers of protection against influenza. Instead due attention must associated with HPV. be given to personal hygiene, frequent washing of hands, social distancing, use of proper masks, etc. should not give a false sense of security.27 Influenza Vaccination In various studies it was found that high-dose vaccine Influenza (flu), which caused a pandemic in 2009 (fluzone) was 24.2% more effective (CI 9.7–36.5%) in accounting for 100,000–400,000 deaths, still remains preventing flu in adults 65 years of age and older relative a cause of global concern. According to the World to a standard-dose vaccine28 and high-dose influenza Health Organization (WHO), 1 billion cases surface vaccine can reduce risk of respiratory-related hospital every year globally, causing about 200,000–600,000 admissions from nursing home residents aged 65 years 25 deaths. According to Flu Net, the WHO Global Influenza and older.29 Surveillance and Response System (GISRS) laboratories; In people who received vaccination in two consecutive out of total cases 98.6% were influenza A and 1.4% were seasons, protection against H3N2 was lesser than influenza B cases. Out of these influenza A viruses, those who had only been vaccinated in current season 65.2% were influenza A H1N1 and 34.8% were influenza suggesting that repeated vaccination against influenza A H3N2. Influenza A H3N2 infection was more virulent may weaken the immune system30 However, as per CDC than influenza A H1N1. In India also the strain influenza recommendations, annual flu vaccination remains the A (H1N1) has accounted for most cases—which peaked first and most important step in protecting against flu in the third week of February 2019.23 Although the report and its complications. One of the studies31 postulated that said that vaccination was the most effective tool to create twice annual influenza vaccinations in elderly population immunity against the disease, but certain doubts remain of tropical and subtropical areas has improved efficacy. there about vaccination. However, the observations were in contradiction to the „„ Which type of vaccination in India should be used? above said postulation. Northern hemisphere/Southern hemisphere. „„ High dose versus routine dose in 65 year plus people 32 (High dose vaccination not available in India). Future Vaccine Considerations „„ Serial vaccination and do annual vaccination cause less An ideal universal vaccine should be: immunization in subsequent vaccination? Antigenic „„ Effective for longer duration of time and 75% distancing hypothesis. effective against all strains of Influenza A virus in all „„ Universal vaccination: Will single vaccination for age groups. lifetime (like other vaccines) see some light in time to „„ A cell based or a recombinant formulation should be come? favored over an egg-based vaccine. „„ The hemagglutination inhibition response for a Seasonal Influenza Vaccine Recommended for the nanoparticle vaccine formulated with a saponin-based 26 Season of 2019-2020 in India adjuvant was greater than a high dose vaccine. In India, ICMR and Ministry of Health and Family Welfare, „„ Traditional influenza vaccine target IgG portion. Government of India, have recommended Northern However, since different parts of IgA trap many parts hemisphere quadrivalent/tetravalent vaccine. of influenza virus simultaneously, IgA may be a more Due to the constant changing of antigenicity, the effective target. efficacy of influenza vaccination is potentiated when „„ Manufacturing time should be shortened.

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Universal Influenza Vaccine Tdap/DTaP Vaccination35,36 A ball and spike model depicts well of a structure of Bordetella pertussis may be the etiologic agent in 12–30% influenza virus where hemagglutinin protein on the of adults with cough that does not improve within 2 weeks. surface represent as spikes. Each spike having a stalk and This is a highly contagious disease with attack rates of a cap. 80–100% among unimmunized household contacts and While all current influenza vaccines target at the cap 20% within well immunized household contacts. Despite portion of the hemagglutinin proteins which change its their efficacy whole-cell pertussis vaccines have been antigenicity frequently requiring annual vaccination. associated with adverse events both common (fever, pain Instead the stalk portion of the hemagglutinin protein is at injection site, erythema and swelling; irritability) and stable among different influenza viruses and does not alter uncommon (febrile seizures, hypotonic hyperresponsive antigenicity annually. Therefore, a vaccine targeted at the episodes). There have also been alleged associations of stalk portion of the hemagglutinin protein can turn out to whole-cell with encephalopathy, sudden be a universal vaccine. infant death syndrome, and autism, which although not substantiated, have succeeded in initiating an active anti- Measles Cases in 20192,33 immunization lobby. It is worth understanding the mechanism of transmission Low dose diphtheria toxin along with acellular pertussis of measles as it is highly contagious like COVID-19 virus. It vaccine in otherwise previous DPT vaccine has reduced its has been noted that the viability of the virus lasts for about dreaded side effects. Currently, diphtheria vaccine 2 hours and individuals who have not been vaccinated is coadministered with (with or without against measles have a 90% chance of contracting measles. acellular pertussis). DTaP (full-level diphtheria toxoid, These people now have the potential to spread the disease tetanus toxoid, and acellular pertussis vaccine) is currently to 9–18 other people.2 However, in the global scenario, recommended for children up to the age of 6 years. DTaP measles is the leading cause of vaccine-preventable replaced the earlier whole-cell pertussis vaccine DTP in disease and deaths despite the widespread use of vaccines 1997. Tdap is formulated for adolescents and adults and and in fact every year 100,000 people die from measles.2 consists of acellular pertussis, tetanus toxoid and reduced World Health Organization reports that there were 1,234 diphtheria toxoid, and acellular pert Tdap was licensed for cases of measles in the US and 91 cases in Canada from use in the US in 2005 and is recommended for children ≥7 January 2019 to September 2019. On the other hand, in years old and for adults. It is recommended that all adults 2018, 372 cases were reported in the US and 28 in Canada. who have never received Tdap before; a single dose of The recent spike in measles outbreak is due to vaccine Tdap should be given regardless of the fact that they got Td deterrence (out of fear of Autism and ignorance and vaccine before. This should be followed by either a Td or inertia). This along with increase in international travel Tdap booster every 10 years. has facilitated the disease to enter into areas where it was Efficacy of vaccine can be ascertained by certain once considered eliminated.34 historical events. During the 1990s, an epidemic affecting 150,000 people occurred in the former states of the Soviet Current Recommendations for Adults Union out of which 5000 had died. This was associated with a clonally related strain of ET8 complex. This It is advisable for the adults including students at post high outbreak was attributed to the failure of the public health school educational institutions, health-care personnel, infrastructure to vaccinate the people. international travelers who do not have significant evidence of immunity to get a single dose of MMR vaccine. Controversy: In the United States, routine vaccination However, certain adults especially students at post high that started in 1940s led to a 100-fold reduction in the school educational institutions may need two doses incidence of pertussis, and the disease appeared to be on separated by at least 28 days. Also, the killed measles the road to elimination.2 However, since the mid-1970s, vaccine available in 1963–1967 was not very effective. So, the disease has once again resurfaced,2 steadily increasing they should be vaccinated again. in incidence to 15.1 cases per 100,000 in 2012.

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The recent surge of pertussis in developed countries Controversy and Concern39-41 led to a controversy as to its cause. Domenech de Cellès The development of a new vaccine usually takes around et al. modeled the transmission of pertussis using 10–15 years.40 Mumps was the fastest vaccine which was incidence data from Massachusetts, US. They found developed in 5 year time. During this pandemic era there that it was not the switch to acellular pertussis vaccine is lot of pressure by public and government agencies on but rather the waning vaccine conferred immunity that the pharma companies to develop vaccine at a faster pace. contributed to the Massachusetts outbreak This could be Therefore, the vaccines are being developed in a very short explained by the local increased incidences in pertussis period and on trial basis on smaller groups. As a result cases in the subpopulation who were not vaccinated. Simulations suggested that administration of existing boosters to children may be an effective strategy to halt the transmission of pertussis. Current recommendation: Every Adult >10 years of age should be given Tdap followed by booster dose of Td or Tdap every 10 years including pregnant women in early pregnancy.

COVID-19 Vaccination Three types of mechanisms are involved for manufacturing of Covid SARS 2 vaccines (as depicted in Figure 2) which are being developed by more than 300 drug companies. Fig. 2: Vaccine candidates use different mechanisms, such as those shown above, to prompt the body to produce antibodies against As of now following vaccines (Table 2) are at various SARS-CoV-2 38 stage of development: (Source: GAO-20-583SP)

TABLE 2 Vaccine types and current stage of development

Vaccine candidates, Mechanism Sponsor Approved/phase developers, and sponsors mRNA-1273 mRNA-based vaccine Moderna, Pfizer, BioNTech, Fosun zz UK: MHRA (December 2, 2020) Pharma zz Bahrain: NHRA (December 5, 2020) zz Saudi Arabia: SFDA (December 10, 2020) zz US: FDA (December 11, 2020) zz MX: COFEPRIS (December 11, 2020) Ad5-nCoV Recombinant vaccine CanSino Biologics Approved China (adenovirus type 5 vector) AZD1222 Replication-deficient viral The University of Oxford; Phase 3 vector vaccine (adenovirus from AstraZeneca; IQVIA; Serum chimpanzees) Institute of India Bharat Biotech; National Phase 3 Institute of Virology JNJ-78436735 Non-replicating viral vector Johnson & Johnson Phase 3 (formerly Ad26.COV2.S) NVX- Nanoparticle vaccine Novavax Phase 3 CoV2373 Gam-COVID- Vac Non-replicating viral vector Gamaleya Research Institute of Russia: Ministry of Health (Sputnik V) Epidemiology and Microbiology

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when the vaccines are released for public use on mass people and HCP there has been apprehension and doubts scale, the side-effects which were unnoticeable during in the mind of public at large which precludes them of 39 trial phase may become overt. RNA-based vaccines are using vaccines. Affordability of certain vaccines and Inertia a major new tool to combat pandemics like COVID-19 on the part of HCP is another reason for underutilization of outbreaks as they require only viral genetic sequence vaccination. The adverse effects of vaccines are so highlighted information to initiate development. and dramatized by media (including social media) that it In the past DNA and RNA vaccines have not been overshadows the efficacy of vaccinations. Need of the hour successful for human diseases and m-RNA based vaccines is to remove this misconception in mind of people with help will be used for the first time in human being and that too of HCPs, Govt. agencies, media, etc. to help us overcome this menace as was done in case of polio and smallpox. in the pandemic period with trials done for less than a year duration. The vaccine candidates using human adenovirus References as vector such as Cansino Biologics (Wuhan, China) 1. Phadke VK, Bednarczyk RA, Salmon DA, et al. Association between could reduce immune response as there is lot of pre- vaccine refusal and vaccine-preventable diseases in the United 41 existing immunity to Adenovirus. Mutations of virus is States: a review of measles and pertussis. JAMA. 2016;315(11): another important factor that can result in having limited 1149-58. effectiveness of vaccines. There is also concern that . 2 Sanyaolu A, Okorie C, Marinkovic A, et al. Measles outbreak in vaccines may cause antibody dependent enhancement unvaccinated and partially vaccinated children and adults in the United States and Canada (2018-2019): a narrative review of cases. ADE (as was seen in Dengue Vaccines) or antibody Inquiry. 2019;56:0046958019894098. dependent cellular cytotoxicity (ADCC). 3. Hussain A, Ali S, Ahmed M, et al. The anti-vaccination movement: a Response to vaccines may differ in various age groups regression in modern medicine. Cureus. 2018;10(7):e2919. and in people with different status of immunity. During 4. Fitzpatrick M. The cutter incident: how America’s first phase II trial Sanofi’s recombinant DNA derived vaccines led to a growing vaccine crisis. J R Soc Med. 2006;99(3):156. did not yield adequate antibody titer in people aged 50 . 5 The history of vaccines. Available from https://www. historyofvaccines.org/content/articles/history-anti-vaccination- years or more. movements#Source%208 The trial so far has been conducted in non-pregnant . 6 Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular and younger population. Therefore, side effects and hyperplasia, non-specific colitis, and pervasive developmental concerns in extremes of age and pregnancy are still to be disorder in children. Lancet. 1998;351(9103):637-41. decided. . 7 Kulenkampff M, Schwartzman JS, Wilson J. Neurological Cost of vaccine, hesitancy, manufacturing capabilities, complications of pertussis . Arch Dis Child. 1974;49(1): 46-9. logistics, maintenance of cold chain, and transportation . 8 Baker J. The pertussis vaccine controversy in Great Britain, 1974- are other issues which may burden our country in terms 1986. Vaccine. 2003;21(25-26):4003-11. of money and manpower in delivering vaccines to target . 9 Halperin SA, Top KA. Pertussis and other Bordetella infections. In: population. (At the time of submitting of this article Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J FDA has approved Tozinameran (BioNTech, Pfizer) on (Eds). Harrison’s Principles of Internal Medicine, 20th edition. New York: Mcgraw Hill; 2018. pp. 1143-4. 11 December 2020, while on the same day Sanofi has 10. Taylor LE, Swerdfeger AL, Eslick GD. Vaccines are not associated postponed phase III trial due to poor antibody titer in with autism: an evidence-based meta-analysis of case-control and people aged 50 years or more.) cohort studies. Vaccine. 2014;32(29):3623-9. 11. Hviid A, Stellfeld M, Wohlfahrt J, et al. Association between Conclusion thimerosal-containing vaccine and autism. JAMA. 2003;290(3): 1763-6. This is an established fact that due to proper immunization of 12. Baxter R, Bakshi N, Fireman B, et al. Lack of association of Guillain- masses we have been able to either eradicate certain diseases Barré syndrome with vaccinations. Clin Infect Dis. 2013;57(2): like smallpox or polio or incidences of many communicable 197-204. diseases like measles, pertussis, etc. have been brought 13. Confavreux C, Suissa S, Saddier P, et al. Vaccinations and the risk of to minimum. But due to lack of communication between relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med. 2001;344(5):319-26.

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14. Gherardi RK, Coquet M, Cherin P, et al. Macrophagic myofasciitis 28. DiazGranados CA, Kimmel M, Kirby D, et al. Efficacy of high-dose lesions assess long-term persistence of vaccine-derived aluminium versus standard-dose influenza vaccine in older adults. N Engl J hydroxide in muscle. Brain. 2001;124(pt 9):1821-31. Med. 2014;371:635-45. 15. Principi N, Esposito S. Aluminum in vaccines: does it create a safety 29. Gravenstein S, Han L, Mor V, et al. Comparative effectiveness of problem? Vaccine. 2018;36(39):5825-31. high-dose versus standard-dose influenza vaccination on numbers 16. Cohen J. Controversy over dengue vaccine risk. Science. of US nursing home residents admitted to hospital: a cluster- 2019:365(6457):961-2. randomised trial. Lancet Respir Med. 2017;5(9):738-46. 17. The Dengue Vaccine Controversy Explained. Available from https:// 30. Skowronski DM, Chambers C, Serres GD, et al. Serial vaccination biomedicalodyssey.blogs.hopkinsmedicine.org/2019/07/the- and the antigenic distance hypothesis: effects on influenza vaccine dengue-vaccine-controversy-explained/ effectiveness during A (H3N2) epidemics in Canada, 2010–2011 to 18. Rothman AL. Immunity to dengue virus: a tale of original antigenic 2014–2015. J Infect Dis. 2017;215(7):1059-99. sin and tropical cytokine storms. Nat Rev Immunol. 2011;11(8): 31. Tam YH, Valkenburg SA, P M Perera RA, et al. Immune responses to 532-43. twice-annual influenza vaccination in older adults in Hong Kong. 19. Nicol AF, Andrade CV, Russomano FB, et al. Provance: HPV vaccines: Clin Infect Dis. 2018;66(6):904-12. a controversial issue? Jr Braz J Med Biol Res. 2016;49(5):e5060. 32. Jazayeri SD, Poh CL. Development of universal influenza vaccines 20. Indian Parliament Comes Down Hard on Cervical Cancer Trial. targeting conserved viral proteins. Vaccines (Basel). 2019;7(4):169. 33. Paules CI, Marston HD, Fauci AS. Measles in 2019-Going backward. Available from https://www.sciencemag.org/news/2013/09/ N Engl J Med. 2019;380(23):2185-7. indian-parliament-comes-down-hard-cervical-cancer-trial 34. CDC. 2019. https://www.cdc.gov/globalhealth/measles/ 21. Bergman H, Buckley BS, Villanueva G, et al. Comparison of different globalmeaslesoutbreaks.htm human papillomavirus (HPV) vaccine types and dose schedules for 35. Preston NW. Eradication of pertussis by vaccination. Lancet. prevention of HPV-related disease in females and males. Cochrane 1987;1(8545):1312. Database Syst Rev. 2019;2019(11):CD013479. 36. Rohani P, Drake JM. The decline and resurgence of pertussis in the 22. HPV Vaccines. Available from https://www.cancer.org/cancer/ US. Epidemics. 2011;3(3-4):183-8. cancer-causes/infectious-agents/hpv/hpv-vaccines.html 37. Rohani, P (Rohani, Pejman)[ 1,2,3 ] ; Drake, JM (Drake, John M.) 23. Human Papillomavirus Vaccination for Adults: Updated [ The decline and resurgence of pertussis in the US EPIDEMICS Recommendations of the Advisory Committee on Immunization Volume: 3 Issue: 3-4 Pages: 183-188 CrossRefPubMedWeb of Practices. Available from https://www.cdc.gov/mmwr/volumes/68/ ScienceGoogleScholar wr/mm6832a3.htm 38. Omna Sharma, Ali A. Sultan,Hong Ding,and Chris R. Triggle A 24. Newman PA, Lacombe-Duncan A. Human papillomavirus Review of the Progress and Challenges of Developing a Vaccine vaccination for men advancing policy and practice. Future Virol. for COVID-19. Front Immunol. 2020; 11: 585354. doi: 10.3389/ 2014;9(12):1033-47. Available from https://www.medscape.com/ fimmu.2020.585354 https://doi.org/10.3389/fimmu.2020.585354 viewarticle/837990_3 39. Fernando P. Polack et al .Safety and Efficacy of the BNT162b2 mRNA 25. Influenza pandemic is unpredictable and inevitable: WHO. Covid-19 Vaccine. www.nejm.org› doi › NEJMoa2034577 DOI: Available from https://www.downtoearth.org.in/news/health/ 10.1056/NEJMoa2034577 influenza-pandemic-is-unpredictable-and-inevitable-who-63547 40. Han S. Clinical vaccine development. Clin Exp Vaccine Res. (2015) 26. Guidelines for vaccination with influenza vaccine. Available from 4:46–53. doi: 10.7774/cevr.2015.4.1.46 https://vikaspedia.in/health/diseases/common-problems-1/ 41. Zhu FC, Guan XH, Li YH, Huang JY, Jiang T, Hou LH, et al. seasonal-flu/seasonal-influenza-a-h1n1-guidelines-for- Immunogenicity and safety of a recombinant adenovirus type-5- vaccination-with-influenza-vaccine vectored COVID-19 vaccine in healthy adults aged 18 years or older: 27. Vaccines for preventing influenza in healthy adults. Available from a randomized, double-blind, placebo-controlled, phase 2 trial. https://doi.org/10.1002/14651858.CD001269.pub6 Lancet. (2020) 396:479–88. doi: 10.1016/S0140-6736(20)31605-6

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Infections in Critically 157 ILL Patients

Nitin Sinha

Abstract Critically ill patients are prone to many infections due to multiple interventions being carried out in them by means of indwelling catheters, endotracheal tube, etc. These infections lead to increased morbidity and mortality among critically ill patients. It is, therefore, imperative that these are recognized early and treated appropriately. More important than treating these would be to prevent them from occurring. This chapter deals with various infections in critically ill patients, their pathogenesis, diagnostic, and treatment guidelines and also the preventive guidelines.

Introduction certain survey in the United States, 87% of blood stream infections were associated with central lines. In the same Critically ill patients are those who suffer from a critical survey, catheter associated urinary tract infection (CAUTI) illness that requires them to have intensive monitoring. was responsible for 95% of urinary tract infections.1 This intensive monitoring entails them to have complete Mortality attributable to central venous catheter-related dependency on caregivers for their daily activities. infections is 12–25% and mortality attributable to CAUTI These patients often are in coma/drowsy, mechanically is less than 5%.2 ventilated, bed-ridden, and have many indwelling catheters. These factors make these patients prone to A biofilm formation is critical in pathogenesis of infections, which can be multi-drug resistant. This chapter catheter-associated infections. A biofilm is basically deals with different infections that can occur in critically composed of a conditioning film (formed by the body fluid ill patients, their pathogenesis, and their preventive bathing the catheter) and the microbes that attach to it strategies. (sessile), which secrete an extracellular polysaccharide matrix on the condition film. This biofilm facilitates Different Types of Infections growth of microbes of different species and it is from here that some microbes become mobile (planktonic) and lead Seen in Critically Ill Patients to infections. The biofilm leads to decreased penetration Catheter-associated Infections of antibiotics, local alteration in the microenvironment leading to decreased susceptibility to antimicrobials and Pathogenesis and Risk Factors antimicrobial resistance. Many microbiological culture Critically ill patients mostly have multiple catheters results are only of planktonic organisms and these do inserted. It may be urinary catheter, peripheral intravenous not apply to sessile organisms embedded in the biofilm. cannula, arterial catheter, or central venous catheter. It is because of this that sometimes antibiotics merely These help in critical monitoring of the patient. In a suppress the infection.2

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The intravascular catheters get infected on their are catheter colonization, phlebitis, exit site infection, and outer surface by the microbes present on the skin, blood stream infections. The details regarding all these especially within 10 days of the insertion. So, short- can be read from the guidelines. From the guidelines it term intravascular catheters like peripheral intravenous was noteworthy that catheter tips should be cultured only cannula, arterial catheters, and non-cuffed central venous quantitatively and not qualitatively and that catheters to catheters mainly get contaminated on outer surface. be cultured only after removal. The common organisms that migrate to outer surface of catheters from skin are coagulase negative staphylococci Diagnosis of CAUTI and Staphylococcus aureus. The hub of intravascular The 2009 IDSA Guidelines define CAUTI in catheterized catheters gets contaminated by microbes that chiefly (urethral, suprapubic, and condom) patients and in those come from caregiver’s hands. This especially occurs if in whom catheter (urethral, suprapubic, and condom) the catheter is in situ for greater than 30 days or more. has been removed in last 48 hours by the presence of Intraluminal spread to catheter can also occur from a symptoms and signs of urinary tract infection with no distant source (e.g., urinary tract) or from an infected other identified source of infection and having 1,000 infusate. Most common organisms implicated in these or more colony-forming units (CFU)/mL of 1 or more instances are Stenotrophomonas, Candida, Pseudomonas, bacterial species.5 enterococci. Immune compromised and elderly patients are more likely to develop contamination. Multilumen Pulmonary Infections intravascular catheters and catheters inserted at femoral site are more likely to get contaminated. Internal jugular Definitions, Etiological Agents, and Risk Factors central venous catheter is more likely to get contaminated Pulmonary infections are major causes of mortality than the subclavian counterpart. Peripheral intravenous in critically ill patients. Among intubated patients, lines are more likely to get contaminated if inserted in ventilator associated pneumonia (VAP) diagnosis is lower extremities. Catheters inserted by non-sterile/ made if pneumonia develops 48 hours after intubation.6 2 improper techniques are more likely to get contaminated. Any pneumonia other than VAP developing in hospital The urinary catheter can also get externally is called hospital-acquired pneumonia (HAP).7 VAP contaminated either at the time of insertion or later by occurrence rates are quite different in different studies. fecal matter. Intraluminal contamination can occur by This is due to use of different diagnostic criteria, variations reflux of microbes from the container bag or due to a break in study population, differential evaluation of radiological in collecting system. Commonly isolated organisms are images, and different methods of sampling. Fever, Escherichia coli, Pseudomonas, Enterobacter, Candida, leukocytosis, purulent secretions, new infiltrates on 2 Klebsiella, and enterococci. Staphylococcous and chest x-ray/worsening infiltrates on chest X-ray carry coagulase negative staphylococci have also been isolated. high sensitivity in suspecting VAP, but at the cost of low As with intravascular catheters, immune compromised specificity. Clinical Pulmonary Infection Score (CIPS) patients are more likely to develop contamination. of greater than 6 strongly suggests VAP.8 Common risk The other risk factors for developing bacteriuria in factors for developing VAP are advanced age (>60 years), catheterized patients is longer duration of catheterization, male gender, increased mechanical ventilation time (>2 diarrhea, female gender, renal insufficiency, improper weeks), prolonged hospital stay, altered consciousness, 3 catheter insertion technique, and improper catheter care. burns, comorbidities (diabetes, CAD, COPD, chronic renal failure, Hashimoto’s thyroiditis), prior antibiotic Diagnosis of Catheter-related Blood use (leading to MDR pathogen infection), placement of Stream Infection (CRBSI) gastric tubes, invasive procedures in ICU (reintubation, The Infectious Disease Society of America (IDSA) has tracheostomy, fiberoptic bronchoscopy), smoking, published updated detailed guidelines for diagnosing raised intra-abdominal pressure, hypoxia, and gene intravascular CRBSI in 2009.4 The commonly used polymorphisms (single nucleotide polymorphisms of terminologies for intravascular catheter-related infections TNFα gene, ATG16L1 gene, and TREM 1 gene). Commonly

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organisms causing early VAP (occurring within first blisters were most commonly observed dermatoses, and 4 days of hospitalization) are Enterobacteriaceae and maculopapular drug eruption was the commonest drug Staphylococcus aureus and those causing late VAP reaction observed.11 are non-fermenting bacteria and Enterobacteriaceae. Almost similar findings (though with different Acinetobacter baumannii, Pseudomonas aeruginosa, E. proportions) were observed in patients admitted in coli, and Klebsiella are commonly isolated. Mortality from Medical ICUs. The only difference from surgical ICU early VAP is nearly 19% and that of late VAP is 31.4%.6 patients was that fungal skin infection was the most Common organisms causing HAP are Pseudomonas commonly observed infectious dermatological lesion. aeruginosa, S. aureus, Klebsiella pneumonia, E. coli, Mortality was significantly more in those who had S. marcescens, Stenotrophomonas maltophilia, and dermatological lesions as compared to those who did Acinetobacter baumanii.9 not.12

Diagnosis of VAP and HAP7 Treatment Diagnosis of VAP should be made preferably Treatment of any infection that develops in a critically by noninvasive sampling (endotracheal aspiration, ill patient depends upon the etiology, site, severity, and spontaneous expectoration) rather than invasive sampling antibiotic sensitivity. Some infections like cellulitis, [protected specimen brush (PSB), bronchoalveolar lavage fasciitis may also require surgical intervention. Catheter (BAL), and blind bronchial sampling (mini-BAL)]. Also, removal might sometime need surgical assistance. semiquantitative culture should be used for diagnosis. Empirically started antibiotics must be according to the Diagnostic threshold for diagnosing VAP is more than 103 antibiogram of the hospital/institute. CFU/mL by PSB or more than 104 CFU/mL by BAL.

Dermatological Infections Prevention of Infection in Skin infections are also common in critically ill patients. In Critically Ill Patients a study by Malheiro et al. in ICU patients, it was observed This is the utmost important part in critical care. Prevention that immunosuppressive drug use, intravenous drug is always better than cure. abuse, Type 2 diabetes mellitus, previous cutaneous or

soft tissue infection (STI), HIV, cirrhosis, obesity, renal 13 failure, etc. were risk factors for developing skin and Prevention of CRBSI soft tissue infections.10 They, however, included patients Centre for Disease Control and Prevention has laid down with necrotizing fasciitis, abscesses and cellulitis only. extensive guidelines for prevention of CRBSI. Some salient Fournier’s gangrene and cervicothoracic fasciitis were points are: two most commonly observed fasciitis. Abscesses were „„ Staff should be adequately trained and educated commonest in cervical/thoracic region and cellulitis regarding insertion, care, and removal of catheters. was observed in abdomen and lower limb. Myriad of „„ Peripheral catheters to be inserted in upper extremities. organisms from E. coli to Staphylococcus aureus, Proteus, „„ Use midline catheters/PICC line if duration of Klebsiella, etc. were isolated from different infection sites. intravenous therapy is likely to exceed 6 days. In a prospective analysis of ICU patients admitted „„ Do not remove gauze dressing at insertion site daily. due to surgical causes, 12.1% developed dermatological Palpate the site for any tenderness or swelling. Remove disorders out of which 28.8% had infectious dermatological peripheral catheter if there are signs of phlebitis. lesions, 26% had dermatosis and 45.2% had drug „„ Use subclavian site for central venous catheter (CVC) reactions. Longer ICU stay (>10 days) was associated insertion for nontunneled catheters to minimize more with dermatological disorders. Comorbidities like infection. There is no recommendation for site for diabetes, CAD, hypertension, etc. were commoner in tunneled CVC insertion. patients who developed dermatological disorders. Wound „„ Use CVC with minimum ports. infection was the commonest infection observed, frictions „„ Remove CVC as soon as its use is over.

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„„ Perform hand hygiene before and after catheter indwelling catheter. Intermittent self-catheterization insertion, dressing, removal, guide wire change or can be done in patients with bladder dysfunction or catheter site palpation. This can be achieved by with spinal cord injury. washing hands with soap and water or by applying „„ Catheterization to be done by well-trained persons alcohol based hand rubs (ABHR). and hand hygiene to be practiced prior to insertion „„ Use maximum sterile barrier precautions (sterile or after any manipulation of the catheter. Sterile gown/drape, sterile gloves, mask, and cap) while technique to be used for insertion of catheter which inserting arterial catheter, PICC, or CVC. entails using sterile gloves, gowns, and sponges „„ Insert CVC preferably by using ultrasound. and cleaning of periurethral area with appropriate „„ Clean skin with antiseptic (70% alcohol, tincture of antiseptic solution. There is no need to use antiseptic iodine or alcoholic chlorhexidine gluconate solution) lubricants routinely. Catheter needs to be secured before peripheral venous catheter insertion. Prepare adequately after insertion. clean skin with more than 0.5% chlorhexidine „„ Maintain a closed drainage system. Avoid kinking of preparation with alcohol before inserting CVC, PICC, catheter and collecting tube and ensure that collecting or arterial catheter. bag does not rest on the floor. Collecting bag to always „„ Use 2% chlorhexidine wash for patients daily skin be below the level of urinary bladder. Empty the cleansing. container bag regularly using separate clean container. „„ Use a chlorhexidine/silver sulfadiazine or minocycline/ There is no role of systemic antibiotic prophylaxis rifampin-impregnated CVC if the catheter is likely to while catheter is in-situ. There is again no role of be in place for more than 5 days and only if the Central putting antiseptic/antimicrobial solution in collecting Line Associated Blood Stream Infection (CLABSI) bag routinely. There is no recommendation for using rate is not decreasing despite using a comprehensive urinary antibiotic (methanamine). Routine use of any strategy, which at least should include these three catheter with antibiotic release cartridge installed in components: educating persons who insert and the catheter’s drain port is not necessary. There is no maintain catheter, using maximum sterile barrier need to clean periurethral area with antiseptic solution precautions (as detailed in point 9) and more than daily when catheter is in place; cleaning of meatal area 0.5% chlorhexidine preparation with alcohol for skin while daily bathing/sponging is sufficient. preparation before CVC insertion. „„ Use antibiotic impregnated catheters only, if CAUTI „„ There is no need to use antibiotic prophylaxis while rate is not improving despite using a comprehensive catheter is in-situ. Also, there is no need to use strategy. anticoagulation. „„ Silicone catheter might be preferable over other „„ Use antibiotic lock solution prophylaxis in patients who catheter materials in long-term catheterized patients have long-term catheters and have history of multiple who have frequent obstruction as it prevents CRBSI despite optimal and maximal adherence to encrustations. Hydrophilic catheter might be aseptic precautions. preferable to standard catheter in patients requiring Certain recommendations (apart from those intermittent self-catheterization. mentioned above) in CDC guidelines were changed/ added in 2017. The details can be checked from CDC 15 website. Prevention of VAP VAP can be prevented by following methods: 14 Prevention of CAUTI „„ Avoid intubation, if possible. Use noninvasive positive „„ Insert catheter only for appropriate indication and pressure ventilation (NIPPV). leave in place for only as long as needed. Even for „„ Minimize sedation. Try to give off to sedation once a operative patients, use catheter only if required. day (awakening trial). Give spontaneous breathing „„ In males with bladder outlet obstruction/urinary trials. Try to club the two trials together. retention, consider using external catheter in place of „„ Provide early exercise and mobilization.

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„„ Use endotracheal tubes with subglottic secretion . 5 Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, draining ports if intubation is likely to last for greater and treatment of catheter-associated urinary tract infection than 48–72 hours. in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis. „„ Elevate head end of the bed to 30–45 degrees. 2010;50(5):625-63. „„ Change ventilator circuits only if visibly soiled. . 6 Wu D, Wu C, Zhang S, et al. Risk factors for ventilator-associated „„ There are certain special approaches but they have pneumonia in critically ill patients. Front Pharmacol. 2019;10:482. insufficient data. These are selective oral or digestive . 7 Kalil AC, Metersky ML, Klompas M, et al. Management of adults decontamination, regular oral care with chlorhexidine, with hospital-acquired and ventilator associated pneumonia: and use of prophylactic probiotics. 2016 clinical practice guidelines by the Infectious Disease Society of America and American Thoracic Society. Clin Infect Dis. „„ Certain approaches like using ultrathin polyurethane 2016;63(5):61-111. cuff endotracheal cuffs, saline, automated control of 8. Canon B, Kubilay D, Okcu O, et al. Ventillator-associated pneumonia endotracheal cuff pressure, saline instillation before in critically ill patients with intensive antibiotic usage. Pak J Med Sci. tracheal suctioning, and mechanical tooth brushing 2015;31(6):1441-6. have low quality evidence to prevent VAP. 9. Cunha BA, Brusch JL. Hospital acquired pneumonia and ventilator- acquired pneumonia. Available from https://emedicine.medscape. com/article/234753-overview#a3 [Accessed July 30, 2020] Conclusion 10. Malheiro LF, Magana R, Ferreira A, et al. Skin and soft tissue infections in the intensive care unit: a retrospective study in a Infections in critically ill patients can increase the morbidity tertiary care centre. Res Bras Ter Intensiva. 2017;29(2):195-205. and mortality in these patients. Appropriate preventive 11. Pektas SD, Demir AK. Prospective analysis of skin findings in measures can curtail occurrence of such infections. surgically ill patients intensive care unit. Indian J Dermatol. 2017;62(3):297-303. 12. Pektas SD, Demir AK. Prospective analysis of skin findings in References medical critically ill patients intensive care units. Indian J Dermatol. . 1 Richards M, Edwards J, Culver D, et al. Nosocomial infections 2017;62(3):297-303. in medical intensive care units in the United States. National 13. O’Grady NP, Alexander M, Burns LA, et al. Guidelines for the Nosocomial Infections Surveillance System. Crit Care Med. prevention of intra-vascular catheter related infections, 2011. 1999;27(5):887-92. Available from https://www.cdc.gov/hai/pdfs/bsi-guidelines-2011. . 2 Trautner BW, Darouiche RO. Catheter-associated infections. Arch pdf [Accessed July 29, 2020] Intern Med. 2004;164(8):842-50. 14. Gould CV, Umscheid CA, Pegues DA, et al. Guidelines for prevention . 3 Brusch JL. Catheter-related urinary tract infection. Available from of catheter-associated urinary tract infection, 2009. Available from https://emedicine.medscape.com/article/2040035-overview https://www.cdc.gov/infectioncontrol/guidelines/cauti/index. [Accessed July 26, 2020] html [Accessed July 29, 2020] . 4 Mermal LA, Allon M, Bouza E, et al. Clinical Practice Guidelines 15. Klompas M, Branson R, Eichenwald EC, et al. Strategies to for diagnosis and management of intra-vascular catheter related prevent ventilator-associated pneumonia in acute care hospitals: infection: 2009 update by the Infectious Disease Society of 2014 update. Available from https://www.jstor.org/stable/ America. Clin Infect Dis. 2009;49(1):1-45. pdf/10.1086/677144.pdf [Accessed July 29, 2020]

MU-157.indd 1027 29-01-2021 15:11:01 CHAPTER

Current Controversies in 158 Sepsis Management

Atul Bhasin, RK Singal

Abstract Sepsis syndrome, a dysregulated host response in infection, has multimodality and multifaceted treatment which has been changing over the decades since its recognition. Advances in management of the syndrome brought along with it many controversies and failures in treating it. The advances made in treatment kept changing with emergence of newer definitions, its assessment scores, role of infusion and combination empiric antibiotic therapy. The prognostic value of biomarkers to guide duration of antibiotics, fluid therapy, its role in endothelial glycocalyx protection along with antioxidant therapy and steroids is being evaluated.

Introduction syndrome of a dysregulated host response to infection. As of 1991, the initial definition stated that systemic Sepsis is a life-threatening syndrome of a dysregulated inflammatory response syndrome (SIRS) to infection host response to infection. Despite advances in diagnosis would be called sepsis. While subsequent revision of the and treatment, sepsis still remains a significant cause of definitions in 2001 specified the organ damage. Similarly, morbidity and mortality. Many aspects of the diagnosis the new definitions 2016 defined it as a life-threatening and clinical management of sepsis require further organ dysfunction due to dysregulated host response to study and remain controversial. Relevant literature any infection. Later the role of Sequential Organ Failure and controversies regarding the overall evaluation and Assessment (SOFA) was brought in where an organ management of sepsis and septic shock need to be dysfunction is assessed as an acute increase in total SOFA revaluated time and again for management. score by two points as a consequence of infection. Further adding to dilemma, the Sepsis-3 investigators introduced Newer Definitions of Sepsis and a new bedside index, called the quick Sequential Organ Its Impact on Diagnosis Failure Assessment (qSOFA). This was introduced to The last two decades have seen ever changing definitions identify patients evolving into sepsis or could be in early of sepsis, thus creating “more controversies” in the minds sepsis in suspected infections. The qSOFA has just three of bedside clinicians and emergency physicians. The easily measured physiological variables, that is, systolic changing clinical scenarios for the treating physicians at arterial blood pressure ≤100 mm Hg, respiratory rate >21 bedside further add to the already complicated issues of breaths/min and altered mental status (GCS ≤ 13), with labeling the patient in sepsis. The effort to simplify the each receiving one point and range being zero to three. It is definition or criteria for defining sepsis, in recent times, quite obvious that by these parameters there is a tendency has lead to increased diagnosis of this life-threatening to over diagnose sepsis in many patients having above

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variables. As any two of these constitute a “positive” result care policies of the region. This will specifically target and and an indication that the patient is at risk of sepsis. The reduce the mortality and morbidity in a particular region difficulty here is that it has a very low threshold (all that is due to endemic diseases causing critical illnesses. needed is tachypnea and a slightly low blood pressure) to Abandoning terms like severe sepsis, septic shock, over diagnose sepsis. It needs to be understood that it is MODS, and septicemia have further widened the not a surrogate definition of sepsis but just an indication difference in concept of ideal or specific management of increased risk. strategies of these illnesses. Emergency physicians need to Though this was a step to increase specificity of think more broadly and initiate appropriate management definition and has eliminated SIRS as was there in previous strategy on the basis of differential diagnoses, which is definitions, but it still has its own deficits. In absence of important factor in management and this has obviously gold standard definition, the clinicians still adopt various been neglected in initial resuscitation strategies. In parameters to diagnose sepsis by combining non-specific our endeavor to simplify criteria, there is a deficit in physiological and laboratory anomalies. understanding disease pathophysiology and its impact on Similarly, the statement of definition as “life- management strategies. The practical guidelines for the threatening organ dysfunction caused by a dysregulated management in accordance with specific etiologies and host response to infection” is more controversial in organ involvement need to be considered and managed defining the terms like life-threatening, dysregulated, accordingly. quantitative assessment of dysregulation. Though the new Sepsis-3 definitions have reduced Combination Empiric Antibiotic Therapy complexity, removed terms like severe sepsis, defined Combination of antibiotics is usually initiated on a clinical the role of qSOFA and has helped the emergency team diagnosis of sepsis and this is usually done with broad categorize patients early into sepsis but still has major spectrum antibiotics, in optimal doses. This is done with drawbacks. The controversies around microbiological a view to have maximal coverage with a perspective to de- confirmation, quantitative assessment of dysregulated escalate once the organism is recognized and antibiogram syndrome, a syndromic approach, and over sensitivity available for further management. Though there are both of qSOFA remains to be further evaluated in bedside advantages and disadvantages of using combination practices and epidemiological studies. therapy, but no measurable survival benefit has been seen on routinely using a combination therapy except in few Sepsis or Septic—Is there a Difference instances. The current recommendations for combination in Assessment therapy as per Surviving Sepsis Campaign are only meant The word “Sepsis” is being confused with “being septic.” for the neutropenic patients, patients with suspected As understood over the decades, sepsis by definition multidrug resistant organisms especially (Acinetobacter is bacteriological culture positivity of disease in any or Pseudomonas) and respiratory failure with sepsis. previously sterile body tissues or blood. While the word Though the combination therapy, for many multidrug Septic signifies presence of any viral, protozoan, fungal, resistant Gram-negative sepsis infections, is essential, but or any other illness leading to a diseased state. While this cannot be followed as rule in light of studies suggesting SIRS also included non-infectious cause’s of sepsis that combination therapy was only effective if the drugs syndrome. Simplicity of the term sepsis, defined as an were effective in vitro too. Thus negating the suggestion invasion of normally sterile tissue or fluid or body cavity by that combination was always logical, as together the pathogenic or potentially pathogenic microorganisms can combinations overcome the so-called target attainment never be disputed, in spite of the fact that a microbiological minimum inhibitory concentration (MIC) threshold, confirmation is difficult at times. All the definitions of despite in vitro resistance. The definite advantage of sepsis do not differentiate or distinguish between viral, combination therapy in form of a broad spectrum of parasitic, and other causes of sepsis. Similarly, regional activity, reduction in development of drug resistance, and infections, which necessitate the treatment variations, also synergism can never be denied but all this adds to the risk need to be catered to especially when planning the health- of toxicity, super infections, and additional cost.

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Antibiotics Infusion in Sepsis adequate antibiotic therapy is whether the physician can de-escalate it. And obviously the answer stands to a good Different antibiotics differ in their mechanism of action, reason of clinical assessment. and in the case of β-lactams, the time above the MIC As per recommendations of the Surviving Sepsis (T > MIC) (i.e., the duration of time that the antibiotic Campaign all biomarkers, including procalcitonin can be concentration in the relevant tissue space exceeds the used by clinicians to assist him in withdrawal of antibiotics minimal inhibitory concentration required to kill the in septic patients especially those who have not been bacteria) is the critical pharmacokinetic characteristic that proven to have an infection on subsequent investigations determines its efficacy. This makes it pharmacokinetically after the initial therapy under septic bundle protocol more effective if it is administered as a continuous infusion therapy. to optimize the T > MIC. Dulhunty et al. showed that continuous infusion improved the pharmacokinetics but it did not improve the ICU survival rate or the statistically Procalcitonin significant clinical cure.1 Similarly, the BLISS trial reached Among other biomarkers Procalcitonin has been nearly, identical conclusions. A meta-analysis of 632 advocated the most. Procalcitonin is up regulated by the patients concluded that there was a statistically significant cytokines that are secreted in bacterial infections in sepsis. benefit of continuous infusion for both the clinical cure Thus ideally it should not be used as guide in such patients, and its survival benefits. When this was analyzed by especially as a guide to decision-making regarding multivariate analysis the independent effect of continuous initiation of antibiotics. However, its use as in guiding de- infusion was lost. Arguably it stands to reason that this escalation of antibiotic therapy after initial rise has more intervention improves the clinical cure of infection, but as significance. All the studies, that is, PRORATA, ProGUARD, the survival of critically ill patient is a multifactorial variant and SAPS trial’s found a non-significant reduction in days thus the outcome may not be as expected in view of its of antibiotic use in their intervention arms, while the dependency on various other factors.2 impact on mortality showed no differences. However, in view of false positive levels in non-infectious inflammatory Biomarkers to Guide Duration diseases and false negative in severe infections clinical of Antibiotics decision and judgment should always be used to override the importance of serum levels.3 Duration of an antibiotic therapy has always been based on the evidence of clinical course, cure, and the outcome of the infectious disease being treated. The duration Fluid Therapy and Its Role in Endothelial of antibiotic therapy has been, as controversial as its Glycocalyx Protection initiation without a documented infection, and that too As controversies in fluid resuscitation in sepsis and septic in critically ill patients. Though there is no conflict on the shock exist even after three decades of active management, general principle that, it should be given for the shortest it is still eluding the question whether, under or over duration, but the exact duration of therapies have always resuscitation is beneficial or not for sepsis management. been controversial except in few clinical conditions. The Endothelial glycocalyx, an endothelial cell surface same holds for the patients being treated in critical care layer composed of membrane anchored proteoglycans units. and heparan sulfate, essentially acts as a endothelial The role of biomarkers in the last decade have changed barrier and opposes leukocyte-endothelial adhesion.4 the guidelines and treating principles, but the controversies During sepsis, activation of heparanase in vessel wall in their potential use a sole criteria to guide a therapy also leads to degradation of glycocalyx heparan sulfate thus exist. The role of procalcitonin has been much studied, furthering the endothelial dysfunction and injury caused with over more than eight thousand papers defining its due to sepsis. A hormone, released due to volume loading role in treatment of sepsis. The question which haunts any causing atrial stretching, that is, atrial natriuretic peptide treating physician after the normal Procalcitonin report is furthers the degradation of endothelial glycocalyx, whether the patient is infected and should an antibiotic thus aggravating the septic vasoplegia. Though this be withheld. In case of abnormal reports even after phenomenon has not been explored much in humans,

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but animal models have proved beyond doubt the amount all cause mortality in 90 days. Similarly, steroids therapy of injury caused and the aggravation of the vasoplegia. was associated with more-rapid resolution of shock and Intravenous fluid resuscitation is associated with septic shorter duration of ICU stay. Therefore, in respect to endothelial glycocalyx degradation. As expected, injurious above, an adjunct dose with 200 mg per day intravenous effects of fluid therapy following resuscitation would therapy was used in a study.8 worsen the outcome primarily by causing microcirculatory dysfunction. The potential beneficial hemodynamic effects of fluid resuscitation, thus being negated. Several recent Antioxidant Therapy with Vitamin C randomized trials have demonstrated such worsening and Thiamine 5 of sepsis after initial bolus intravenous fluids. The exact Protective effects of vitamin C against oxidative-stress- mechanisms by which such harm is caused need to be mediated cell damage and organ dysfunction in sepsis further evaluated and documented. Few studies also and septic shock are well known.9 Similarly, its deficiency documented an association between volume of fluid has been observed in critically ill patients. During sepsis used in resuscitation and intubation in high risk patients there is production of reactive oxygen species leading to of heart failure, ESRD and Cirrhosis having sepsis. But endothelial injury and dysfunction, which is seen along similarly no differences in such events were detected in with mitochondrial injury and both of these together lead these patients who had received as per recommended to organ failure. guideline of 30 mL/kg of fluid for initial therapy. Antioxidant activity of vitamin C helps in scavenging free radicals prevents production of the reactive oxygen Steroids in Sepsis species, acts as a neuroprotector, and helps as cofactor for The immunosuppressive effects of steroids have harmful synthesis of vasopressors, thus reducing the oxidant injury effect on severe sepsis but its role as anti-inflammatory and to vessel walls in sepsis. As humans cannot synthesize vasoactive substance cannot be denied. The controversies vitamin C, there develops a state of hypovitaminosis on the dose and duration are the most important issues due to increased vitamin C consumption and reduced in the management of sepsis. Though the harmful effects recycling, which needs to be corrected. This deficient state of high dose therapy have been well documented, but its can only be restored efficiently with parenteral high-dose therapeutic effects in low dose in sepsis are also less clear. administration. The critical illness-related corticosteroid insufficiency Decrease in multi-organ failure and improvement has been well known. The ongoing efforts to prove the in SOFA scores was documented in critically ill patients insufficiency as a diagnostic modality and the therapeutic when treated with high dose of the antioxidants like options to correct have neither been proved or validated.6 vitamin C and E. Marik et al. in study concluded in 2017 The two studies, CORTICUS in 2008 and HYPRESS in 2016, that there was a significant decrease in mortality when evaluated the low-dose hydrocortisone versus placebo vitamin C, hydrocortisone, and thiamine were used.10 Two for their role in sepsis. Both the studies could not show prospective trials are currently underway that may shed any survival benefit over 28 days. Corticus trial did show more light on the efficacy of vitamin C as a treatment for faster resolution of shock but there was a non-statically sepsis. significant increase in infections within the corticosteroid Similarly, thiamine levels are reduced in 20–70% of the arm. Various other trials also lacked the uniformity in septic patients, and this is associated with worse outcome. proving efficacy of steroids with respect to improvement Thiamine deficiency decreases the activity of enzyme in the severity of shock; along with ideal time of initiation involved in aerobic glycolysis, Krebs cycle, and pentose of this therapy.7 Similarly, the duration and dose of therapy phosphate pathway. These in turn lead to reduced ATP could not be ideally evaluated. The Surviving Sepsis production. ATP helps in maintenance of cellular pH Campaign guidelines in 2016 recommended the use of this and preservation of neurotransmitters both of which are therapy in septic shock refractory to fluid resuscitation. important for cellular metabolism in critical illnesses. The meta-analysis of various studies showed reduction in Thiamine also helps in protecting the kidneys from oxalate 28-day mortality but such an effect could not be proven in nephropathy due to high-dose vitamin C. Thus, thiamine

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played an important role in improvement of renal function Conclusion without any impact on mortality.11 Hydrocortisone and vitamin C, both together Sepsis a multifaceted disease needs to be managed with improved the endothelial barrier and microcirculation, simpler and universal guidelines, which are appropriate and can be delivered at all categories of health-care system. Initial and therefore together they increase the production of approach needs to be aggressive and time bound even if catecholamines and thus augment its vasopressor effects. diagnosis is underway as per clinical bedside guidelines and Vitamin C also restores glucocorticoid expression of the clinical scenario. Initial resuscitation with fluids and in the vitamin SVCT2 transporter thus in turn improving responsive patients the fluid therapy needs to be modified. 12 glucocorticoid receptor function. And similarly both Role of vasopressor is well documented and it should not be when combined showed higher in vitro barrier-protective denied early in treatment with its weaning as per documented effect after lipopolysaccharide exposure.13 response. Initial antimicrobial therapy with a goal to target pathogens found in the suspected disease followed by change Choice of Vasoactive Agents in antibiotics as per antibiogram and susceptibility should be done. Antimicrobial therapy guided by the relevant biomarkers Several vasoactive agents can be used to support perfusion reduction should be administered for a total duration of in septic shock. Catecholamines and vasopressin both 7–10 days. Though, this can be of shorter or longer duration function by stimulation of cardiac contractility and/or as per the clinical scenarios. Antioxidants and steroids have peripheral vasoconstriction, depending upon individual been documented to improve the outcomes and should be mechanism of actions. The Surviving Sepsis Campaign administered till further studies evaluate their role. suggests norepinephrine, a potent agonist of both alpha and beta receptors, as the initial vasopressor of choice References in septic shock. Norepinephrine is an endogenous . 1 Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of catecholamine that stimulates alpha and beta receptors, beta-lactam antibiotics in severe sepsis: a multicenter double blind, while dopamine an endogenous catecholamine stimulates randomized controlled trial. Clin Infect Dis. 2013;56:236-44. dopaminergic alpha, and beta receptors. Initiation of 2. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion vasopressor therapy after initial fluid resuscitation is done in Severe Sepsis (BLISS): a prospective, two-centre, open labelled to achieve an adequate mean arterial pressure (MAP). randomised controlled trial of continuous versus intermittent beta- Norepinephrine has been used as a first-line vasopressor lactam infusion in critically ill patients with severe sepsis. Intensive 14 Care Med. 2016;42:1535-45. agent for a long now. As per the new recommendations, . 3 de Jong E, van Oers JA, Beishuizen A, et al. Efficacy and safety of the vasopressors should not be delayed until fluid procalcitonin guidance in reducing the duration of antibiotic resuscitation is completed, but should be started rather treatment in critically ill patients: a randomised, controlled, open- early to achieve a target MAP of 65 mm Hg or more. label trial. Lancet Infect Dis. 2016;16:819-27. During the recent decades, terlipressin, vasopressin V1A . 4 Uchimado RSE, Shapiro NI. The glyocalyx: a novel diagnostic and 2+ therapeutic target in sepsis. Crit Care. 2019;23:259. agonist, and even Ca sensitizer have been increasingly . 5 Andrews B, Semler MW, Muchemwa L, et al. Effect of an early used to treat septic shock. A meta-analysis of forty- resuscitation protocol on in-hospital mortality among adults three trials with 5,767 patients assessing seventeen with sepsis and hypotension: a randomized . JAMA. treatment modalities showed vasopressor therapy with 2017;318(13):1233-40. norepinephrine plus dobutamine to be most effective . 6 Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid followed by norepinephrine plus epinephrine or 15 insufficiency (CIRCI) in critically ill patients (Part I). Crit Care Med. terlipressin. The studies have proved beyond doubt that 2017;45:2078-88. norepinephrine should be used as a first-line treatment, 7. Yao Y-Y, Lin L-L, Gu H-Y, et al. Are Corticosteroids Beneficial for Sepsis but when followed by addition of dobutamine it would and Septic Shock? Based on Pooling Analysis of 16 Studies. Front reduce the 28-day mortality. The serious potential adverse Pharmacol. 2019;10:714. effect of precipitating ventricular and supraventricular 8. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378:797-808. arrhythmias needs to be actively monitored during its use . 9 Carr AC, Rosengrave PC, Bayer S, et al. Hypovitaminosis C and especially with individuals having low-cardiac output due vitamin C deficiency in critically ill patients despite recommended to impaired contractility. enteral and par enteral intakes. Crit Care. 2017;21(1):300.

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10. Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, 13. Barabutis N, Khangoora V, Marik PE, et al. Hydrocortisone and and thiamine for the treatment of severe sepsis and septic shock a ascorbic acid synergistically prevent and repair lipopolysaccharide- retrospective before-after study. Chest. 2017;151:1229-38. induced pulmonary endothelial barrier dysfunction. Chest. 11. Moskowitz A, Andersen LW, Cocchi MN, et al. Thiamine as a 2017;152(5):954-62. renal protective agent in septic shock. A secondary analysis of 14. Scheeren TWL, Bakker J, De Backer D, et al. Current a randomized, double-blind, placebo-controlled trial. Ann Am use of vasopressors in septic shock. Ann Intensive Care. 2019;9(1): Thorac Soc. 2017;14(5):737-41. 12. Moskowitz A, Andersen LW, Huang DT, et al. Ascorbic acid, 20. corticosteroids, and thiamine in sepsis: a review of the biologic 15. Cheng L, Yan J, Han S. et al. Comparative efficacy of vasoactive rationale and the present state of clinical evaluation. Crit Care. medications in patients with septic shock: a network meta-analysis 2018;22(1):283. of randomized controlled trials. Crit Care. 2019;23:168.

MU-158.indd 1033 29-01-2021 15:10:29 CHAPTER

Viral Hemorrhagic Fever: 159 Indian Perspective

Ghan Shyam Pangtey, Chinmaya Murthy KR, Paramjeet Singh

Abstract Viral hemorrhagic fevers (VHFs) are a group of severe multisystem syndromes that are caused by several distinct families of viruses. Five distinct families of RNA viruses Arenaviridae, Filoviridae, Bunyaviridae, Flaviviridae, and Paramyxoviridae are well known for various VHFs in different geographic regions. The recent ongoing pandemic of SARS-CoV-2 Coronaviridae virus primarily presents with high-grade fever, cough, and breathlessness due to primary involvement of lungs. But COVID-19 has been found to have multisystem inflammation with Kawasaki Disease like presentation in children, human- to-human transmission, and thromboembolic phenomenon; therefore, it can be considered as emerging VHFs. The CDC- USA defines VHF as acute onset fever (>40°C) with any one of the following clinical finding: severe headache, muscle pain, erythematous maculopapular rash on the trunk with fine desquamation 3–4 days after rash onset, vomiting, diarrhea, pharyngitis (arenavirus only), abdominal pain, bleeding not related to injury, retrosternal chest pain (arenavirus only), and proteinuria (arenavirus only). VHF viruses spread in a variety of ways, but share some common pathogenic features. They have the potential for aerosol dissemination via respiratory droplets and are dependent on an animal or insect host for survival. These viruses are usually restricted to some geographic place of domicile of the host species. After the accidental transmission from the host, human-to-human transmission is possible in some viruses. The mortality rate is highly variable, 0.5% for dengue to 90% for Ebola virus disease. The VHF outbreaks cannot be easily predicted, as they are sporadic and irregular. The blood, urine, vomitus, pus, stool, semen, and saliva from the VHF patient are usually infectious. Barrier nursing practices (such as wearing personal protective equipment) help in reducing the risk of transmission to health-care workers. There is no specific treatment for majority of VHFs, except supportive care.

Introduction with respiratory illness as the primary organ involvement. The properties of multisystem involvement with The term “viral hemorrhagic fevers” (VHFs) depicts Kawasaki like disease presentation, aerosol transmission, a group of diseases that are caused by several distinct human to human spread, and various thromboembolic families of viruses. In general, it is used to describe a phenomenon reported from autopsy series, makes 1 severe multisystem syndrome. The VHFs is mainly COVID-19 a new candidate for VHF. The SARS-CoV-2 caused by six distinct families of RNA viruses Arenaviridae virus has already spread to more than 216 countries and (lassa), Filoviridae (ebola), Bunyaviridae (Crimean- territories and was declared pandemic by WHO on March Congo hemorrhagic fever, CCHF), Flaviviridae (dengue), 11, 2020, it has already caused >550 million infections and Paramyxoviridae (nipah), and Coronaviridae (COVID-19). 13 million deaths worldwide. The SARS-CoV-2 virus (family-coronaviridae) with the Though VHF viruses spread in a variety of ways, they recent pandemic has shown to cause multisystem disease share some common pathogenic features. They have the

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potential for aerosol dissemination via respiratory route Ebola Virus Disease (except dengue), but they are dependent on an animal Ebola virus disease (EVD) is a rare, but deadly disease or insect host for survival. However, these viruses are commonly affecting humans and non-human primates. geographically restricted to the place of domicile of the The EVD viruses are mainly located in sub-Saharan host species. After the accidental transmission from the Africa and their periodic emergence has caused several host, human-human transmission is possible in some outbreaks in African countries. The EVD gets transmitted viruses. VHF may impair the blood clotting ability and to humans through direct contact with an infected animal can also damage the walls of small blood vessels.2 The (bat or non-human primate) or a sick or dead person mortality rate of viral hemorrhagic fever ranges between 3 infected with the virus. Ebola virus was first described in 0.5–90%, depending on the pathologic agent. The VHF 1976 near the Ebola River, which currently belongs to the outbreaks cannot be easily predicted, as they are sporadic Democratic Republic of Congo (formerly Zaire). and irregular. In 1995, an outbreak of Ebola hemorrhagic fever affected more than 300 people in and around the city of Clinical Criteria for VHF Kikwit, Democratic Republic of the Congo. The outbreak The Center of Disease Control (CDC), USA, has made the caused the death of approximately 80% of the patients and VHF definition (2010).4 A person with acute onset disease more than one-fourth of all the patients were health-care 6 with ALL of the following clinical finding: workers. The 2014–2016 outbreak of EBV caused a mortality „„ A fever >40°C, and rate of up to 80–90%, and the death of many health-care 7 „„ One or more of the following clinical finding: Severe workers were due to human-to-human infection. On headache, Muscle pain, Erythematous maculopapular March 23, 2014, the World Health Organization (WHO) rash on the trunk with fine desquamation 3–4 days reported the EBV disease within the forested rural region after rash onset, Vomiting, Diarrhea, Pharyngitis of southeastern Guinea. It was the beginning of the West (arenavirus only), Abdominal pain, Bleeding not Africa Ebola epidemic, the largest in history. On August related to injury, Retrosternal chest pain (arenavirus 8, 2014, WHO declared the Public Health Emergency of only), Proteinuria (arenavirus only). International Concern (PHEIC), which is designated only The predominant signs and symptoms noted in for events with a risk of potential international spread or 7 common VHFs are listed in Table 1.5 that require a coordinated international response. Over the duration of the epidemic, the disease had spread to seven more countries: Italy, Mali, Nigeria, Senegal, Spain, Predominant signs and symptoms noted in common UK, and the US. TABLE 1 VHFs

Disease Signs and symptoms EBV: Ecology and Transmission Ebola virus Fever, headache, muscle pain, fatigue, weakness, Humans get initially infected with EBV through contact disease diarrhea, vomiting, abdominal pain, conjunctival with an infected animal, such as a fruit bat or non-human injection, chest pain, hemorrhage primate. This is called a spillover event. After the spillover Marburg virus Fever, chills, headache, muscle pain, disease maculopapular rash, nausea, vomiting, chest event, the virus can spread from person to person through pain, sore throat, abdominal pain, diarrhea, the following routes: jaundice, hemorrhage „„ Direct contact (such as through broken skin or mucous Lassa fever Fever, nausea, vomiting, diarrhea, retrosternal membranes in the eyes, nose, or mouth) chest pain, sore throat, muscle pain, enlarged „„ Blood or body fluids (urine, saliva, sweat, feces, vomit, cervical lymph nodes, abdominal pain, bleeding, maculopapular rash, conjunctivitis, headache breast milk, and semen) of a person who is sick with or Crimean-Congo Fever, headache, back pain, join pain, abdominal has died from EVD hemorrhagic pain, vomiting, conjunctival injection, facial „„ Objects (such as needles and syringes) contaminated fever flushing, petechial rash, jaundice, bleeding, with body fluids from a person sick with EVD or the photophobia, sore throat body of a person who died from EVD

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„„ Infected fruit bats or non-human primates (such as „„ Critical phase (may develop following resolution of apes and monkeys) febrile phase, lasts 24–48 hours): Shock, hemorrhage, „„ Semen from a man who recovered from EVD (through organ failure, and acute respiratory distress syndrome oral, vaginal, or anal sex) (ARDS) „„ Handling and consumption of bushmeat (wild animals „„ Recovery phase: Clinical stabilization, may develop hunted for food) confluent rash There is no treatment for EBV and only supportive management can be adopted. Ebola survivors mostly Diagnosis and Management complaint of myalgia and muscle pain even after treatment. Initial diagnosis may be established by clinical suspicion. Serum RT-PCR or viral antigen testing within first week of Dengue Fever illness, followed by enzyme-linked immunosorbent assay Dengue fever, the most important mosquito-borne viral (ELISA), may assist in concluding the diagnosis. disease with global epidemic potential, occurs mainly The national vector borne disease control program in tropical and subtropical areas of the world. The virus (NVBDCP) 2014 guideline revised the case definition is transmitted to humans through the bites of infected and made a new classification with moderate dengue female mosquitoes of the species Aedes aegypti.8 It is (Flowchart 1) and guidelines also modified clinical a mild to fatal disease with no cure and only palliative management of severe dengue with bolus fluid regimen. care. The following factors have contributed to the The bolus infusion of 10–20 mL/kg crystalloid infusion emergence of dengue as the classic disease of 21st century: and frequent monitoring drastically reduced mortality in 10 urbanization, increase in travel/trade, highly efficient and dengue patients with profound shock (Flowchart 2). adaptive mosquito vector, thriving of larvae and adults in urban areas, inability to avoid day biting of Aedes vectors, Chikungunya Fever and difficulty in effectively implementing environmental Chikungunya virus is a self-remitting febrile viral illness vector control. transmitted through the bite of infected mosquito A 30-fold increase in the dengue cases has been Aedes aegypti.11 The clinical presentation includes acute recorded globally during the past 50 years, and it is infection, high-grade fever, polyarthralgia (typically associated with substantial social and economic burden.9 bilateral/symmetric, distal > proximal joints), and macular An average dengue episode results in a loss of 14.8 days rash. The severe complications are meningoencephalitis, for ambulatory patients, at an average cost of USD 514. respiratory failure, renal failure, hepatitis, hemorrhagic, However, the mortality rate is less than 0.5%, and it is and heart failure/cardiomyopathy. The disease can be asymptomatic in nearly 80% of the subjects. diagnosed by RT-PCR or serology. Testing for dengue The first evidence of occurrence in India was reported and Zika can also be considered. Management includes in 1956 from Vellore district in Tamil Nadu. In 1996, one supportive care and fluid therapy. Aspirin and other non- of the most severe outbreaks of dengue fever occurred in steroidal anti-inflammatory drugs should be avoided to Delhi, with 10,252 reported cases and 423 deaths. In 2006, reduce the risk of hemorrhage, until patient is afebrile for the country witnessed an outbreak of dengue fever with 48 hours, and there are no additional warning signs for 12,317 cases and 184 deaths. During 2014, a total of 40,571 dengue. cases were reported, which increased to 1,29,166 in 2016 and 1,88,401 in 2017. Zika Virus Infection Zika virus is spread mostly through the bite of an Clinical Presentation infected Aedes species mosquito (Aedes aegypti and The clinical presentation of dengue progresses through Aedes albopictus). Common symptoms of Zika infection the following three phases: include fever, pruritic rash, and arthralgia.12 The severe „„ Febrile phase (4–7 days after exposure): Headache, complications of the disease are Guillain-Barré syndrome eye pain, nausea/vomiting, myalgias, arthralgias, and and neurologic complications including encephalitis macular rash and transverse myelitis. The recent ongoing outbreak

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Flowchart 1: The NVBDCP dengue case definition10

in Madhya Pradesh and Rajasthan (Oct-Nov, 2018) has CCHF infections were reported in the states of Gujarat and claimed two lives. Diagnosis and management strategies Rajasthan.13 are similar to that of dengue and chikungunya. Kyasanur Forest Disease Crimean-Congo Hemorrhagic Fever Kyasanur forest disease virus (KFDV) was first identified Crimean-Congo hemorrhagic fever (CCHF) is caused in 1957 when it was isolated from a sick monkey from by a tick-borne virus (Nairovirus) belonging to the the Kyasanur forest in Karnataka (formerly Mysore) state, family Bunyaviridae. The disease is usually seen in India. Since then, around 400–500 human cases per Crimea, Africa, Europe, and Asia; and human-to-human year have been reported. KFDV is a member of the transmission occurs through direct contact with infectious virus family Flaviviridae. Hard ticks (Haemaphysalis blood/body fluids. In India, the first confirmed case of spinigera) are the reservoir and rodents, shrews, CCHF was reported during a nosocomial outbreak in and monkeys are common hosts for KFDV. The disease Ahmadabad, Gujarat, in January 2011. The outbreak is endemic to South Asia and the human transmission claimed the death of 3 health-care workers due to multiple may occur after a tick bite or contact with an infected organ failure, specifically failure of the liver and kidney. animal. No person-to-person transmission has been During the period of 2012–2015, several outbreaks of reported.

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Flowchart 2: Volume replacement algorithm for patient with dengue with profound shock10

The disease begins with chills, fever, and headache. Nipah Infection Severe muscle pain with vomiting, gastrointestinal Nipah virus (NiV) infection is an emerging zoonotic symptoms, and bleeding problems may occur 3–4 days disease of public health importance in the WHO Southeast after initial onset of symptoms. Patients may experience Asia region. The possible routes of transmission include abnormally low BP, low platelets and red blood cells, and consumption of fruit contaminated by the saliva of leucopenia. However, after 1–2 weeks of symptoms, some infected bats, from direct contact with infected bats or patients recover without complications. their feces/urine. NiV was first recognized in 1998–1999

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during an outbreak among pig farmers in Malaysia fever etc. is another big problem in endemic regions of and Singapore, and it was first recognized in India and vector borne diseases (Table 2).18 Bangladesh in 2001. In July, 2018, a total of 19 NiV cases, including 17 deaths, were reported from two districts in Management of VHF Kerala state (Kozhikode and Malappuram).14 VHFs are a group of distinct RNA viral diseases and it needs individualized care. The EVD has the highest COVID-19 mortality rate, while COVID-19 disease has affected The recent outbreak of COVID-19 in Wuhan city, Hubei maximum number of countries and population. The province, China caused by severe acute respiratory blood, urine, vomitus, pus, stool, semen, and saliva from syndrome Coronavirus 2 (SARS-CoV-2) mainly leads to the VHF patient are infectious. Barrier nursing practices the respiratory illness. The virus is transmitted mainly (such as wearing protective clothing) help in reducing the 15 by respiratory droplets and causes mild symptoms risk of transmission to health-care workers. (asymptomatic/fever/cough/myalgia/sore-throat/ No specific treatment, except supportive care, is anosmia) to severe symptoms (ARDS, shock, respiratory available in most of VHFs. Correction of coagulopathies failure, multi-organ dysfunction) and deaths. The is needed. Antiplatelet drugs and IM injections COVID-19 can cause some cutaneous manifestations are contraindicated due to the risk of hemorrhage. which can be grouped into five major clinical patterns: Investigational treatment approaches include ribavirin „„ Acral areas of erythema and edema with vesicles or for 10 days for arenaviridae and bunyaviridae, and pustules (pseudo-chilblain), convalescent plasma within 8 days of onset for alkhurma „„ Vesicular eruptions, hemorrhagic fever. Upon percutaneous/mucocutaneous „„ Urticarial lesions, exposure to infected blood or body fluids, wash thoroughly „„ Maculopapular lesions, with soap and water, and irrigate mucous membranes with „„ Livedoid or Necrotic lesions. water or saline. Medical surveillance for all potentially This is significant as it tells about the severity with exposed persons is needed for up to 21 days in ebola pseudo-chilblains in mild disease to livedo-necrosis in infection. The surveillance measures include: reporting 16 severe disease. The current epidemiological update hemorrhagic symptoms, recording fever 2×/day, reporting th by WHO for COVID-19 (30 October, 2020) showed temperatures ≥101°F (38.3°C), and initiating presumptive 4,48,88,869 confirmed cases and 11,78,475 confirmed therapy. deaths. The diagnostic laboratory studies are rtPCR, Viral hemorrhagic infection can be prevented using rapid antigen testing, Antibody Testing (IgG,IgM), viral N-95 mask or powered air purifying respirator (PAPR). culture, computed tomography, chest X-ray. Laboaratory Keeping the patient in negative pressure room and using tests of serum LDH, CRP, Serum Ferritin, D-Dimer, and personal protective equipment (PPE) while handling the CBC may be helpful in severe diseases with cytokine patient are essential. The health-care workers should be storm. The various antiviral therapies are only approved trained on the use of PPE. as emergency use authorization with no survival benefit. Steroid and oxygen therapy have been found to be effective in reducing mortality in hypoxic patients with moderate to Assessment for VHF Risk

severe COVID-19 (SpO2 <95%). The general measures for The following CALM (Consider, Act, Laboratory, Monitor) infection control: handwashing, wearing masks, social algorithm is used to assess the risk of VHF infection in distancing, and isolation of infected individuals have been travelers: found to be effective in controlling the infection in hospital „„ Consider: Travelers return from a region endemic for and society. and/or currently experiencing VHF outbreaks are Differentiating COVID-19 from other tropical disease considered infected. (dengue/chikungunya) is a challenge for clinician. „„ Act: Isolate the patient. Limit the health-care workers Similarly, coinfection of COVID-19 with other VHF dengue who enter the room. Appropriate PPE should be

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TABLE 2 Differentiating clinical features between COVID-19 and other similar viral diseases17

COVID-19 Dengue Chikungunya Seasonal influenza Incubation period Ranges 2–14 days (onset Ranges 3–14 days (onset Ranges 1–12 days (onset Ranges 1–4 days (onset of and onset of symptom average 5–7 of symptom average 4–7 of symptom average 3–7 symptom average 2 days). days). Acute onset of low-to- days). Acute onset of high- days). Acute onset of Acute onset of moderate- moderate grade continuous grade continuous fever moderate-to-high grade to-high grade continuous fever continuous fever fever Clinical Cough, dyspnea, fever, Fever, headache, Nausea, Fever rash malaise Fever, cough, sore throat, presentation myalgia, headache, sore vomiting, retro-orbital arthralgia myalgia red eyes and nasal discharge, symptoms throat, diarrhea, abdominal pain, myalgia, arthralgia, headache, myalgia and pain, anosmia, ageusia, rash, bleeding malaise fatigue, confusion Signs Tachypnea, decreased Signs of hypotension Swelling and tenderness Pharyngeal wall hyperemia, oxygen saturation, multi- and shock, hemorrhagic of joints cervical lymphadenopathy organ involvement manifestations (petechiae), positive tourniquet test

Warning signs Respiratory distress SpO2 Persistent vomiting, High grade fever, Respiratory distress SpO2 <94% abdominal tenderness, progressive increase of <94% fluid accumulation, myalgia and arthralgia mucosal bleed Complications ARDS arrhythmias acute Hypotensive shock, Respiratory failure, ARDS myositis cardiac injury shock bleeding, organ cardiovascular rhabdomyolis acute MI pulmonary embolism shock involvement, metabolic decompensation, myocarditis pericarditis acute stroke derangement myocarditis, acute hepatitis, encephalitis myelitis GBS renal failure, hemorrhage, meningoencephalitis acute flaccid paralysis GBS

worn by all personnel entering the patient’s room. References Immediately notify your state/local health department. 1. Viral hemorrhagic fevers (VHFs) | CDC. (2017) Available from https:// „„ Laboratory: Inform the laboratory. Decision to test www.cdc.gov/vhf/index.html for VHF should be made in consultation with relevant . 2 Viral hemorrhagic fevers—Symptoms and causes—Mayo Clinic. health department/CDC viral special pathogens Available from https://www.mayoclinic.org/diseases-conditions/ branch. viral-hemorrhagic-fevers/symptoms-causes/syc-20351260 „„ Monitor contacts: Facilities should maintain a log of all 3. Viral Hemorrhagic Fevers (Internet). (2017). Available from https:// the persons entering the patient’s room, including full azdhs.gov/documents/preparedness/emergency-preparedness/ name and contact information. zebra-manual/zm-s4-vhf.pdf . 4 Viral Hemorrhagic Fever (VHF). (2011) Case Definition. Available from https://wwwn.cdc.gov/nndss/conditions/viral-hemorrhagic- Conclusion fever/case-definition/2011/ VHF is a diverse group of illnesses caused by RNA viruses . 5 Viral haemorrhagic fevers—including symptoms, treatment and belonging to various viral families. Though, the diseases differ prevention: SA Health. Available from https://www.sahealth.sa.gov. by geographic occurrence and vectors/reservoirs, they share au/wps/wcm/connect/public+content/sa+health+internet/ some common clinical features. The diseases are considered conditions/infectious+diseases/viral+haemorrhagic+fevers/ as having international health risk due to their potential for viral+haemorrhagic+fevers+-+including+symptoms+treatment+a aerosol dissemination and human-to-human transmission. nd+prevention Management is only through supportive treatment. Infection 6. Years of Ebola Virus Disease Outbreaks | 2014-2016 Outbreak West control in health-care workers and relatives is of utmost Africa | History | Ebola (Ebola Virus Disease) | CDC. Available from importance. Surveillance of returning travelers by CALM https://www.cdc.gov/vhf/ebola/history/chronology.html algorithm is important to prevent any outbreak in other . 7 Ebola Virus Disease. Available from https://www.who.int/news- geographic area. room/fact-sheets/detail/ebola-virus-disease

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8. Dengue Fever—Symptoms and Causes. Mayo Clinic. Available from Coronavirus (COVID-19). Available from https://www. cdc. gov/ https://www.mayoclinic.org/diseases-conditions/dengue-fever/ coronavirus/2019-nCoV/hcp/index html 2019 symptoms-causes/syc-20353078 16. Galván Casas C, Catala AC, Carretero Hernández G, et al. . 9 A Global Brief on Vector-borne Diseases. (2017). Available Classification of the cutaneous manifestations of COVID‐19: a rapid from http://apps.who.int/iris/bitstream/handle/10665/111008/ prospective nationwide consensus study in Spain with 375 cases. WHO_DCO_WHD_2014.1_eng.pdf;jsessionid=4B2B7C12B5F9E Brit J Dermatol. 2020;183(1):71-7. B5FDAA6680F41669463?sequence=1 17. Guidelines for management of co-infection of COVID-19 with 10. Country Office for India, World Health Organization. (2015). other seasonal epidemic prone diseases by Government of India National guidelines for clinical management of dengue fever. WHO Ministry of Health & Family Welfare Directorate General of Health Country Office for India. Available from https://apps.who.int/iris/ Services (EMR Division) 2020. Available from https://www.google. handle/10665/208893 co.in/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja& 11. Chikungunya Fever. Infectious Disease Advisor. (2016). Available uact=8&ved=2ahUKE wigis6zh4 jtAhXWF3IKHeN1DFg from https://www.infectiousdiseaseadvisor.com/infectious- QFjAAegQIBBAC&url=https%3A%2F%2Fwww. mohfw. diseases/chikungunya-fever/article/610902/ 12. What We Know About Zika . CDC. (2014). Available from https:// gov.in%2 Fpdf%2FGuideli nesformanagementofcoi www.cdc.gov/zika/about/overview.html nfectionofCOVID19withother seasonalepidemicpronediseases. 13. Crimean-Congo Haemorrhagic Fever (CCHF) | National Health pdf&usg=AOvVaw1xHzyRpQkfcl8l4U4qYPMG. Portal of India. Available from https://www.nhp.gov.in/disease/ 18. National Guideline for Dengue Case Management during blood-lymphatic/crimean-congo-haemorrhagic-fever-cchf COVID-19 pandemic. Ministry of Health and Family Welfare, 14. WHO | Nipah Virus Infection. WHO. Available from http://www.who. Government of India on. Available from https://www.researchgate. int/csr/disease/nipah/en/ net/publication/345007787_National_Guideline_for_Dengue_ 15. Centers for Disease Control and Prevention. Novel coronavirus, case_management_during_COVID-19_pandemic_Ministry_of_ Wuhan. China. Information for Healthcare Professionals about Health_and_Family_Welfare_Government_of_India_on

MU-159.indd 1041 29-01-2021 15:09:41 CHAPTER Antimicrobial Stewardship in Clinical Practice—Role of 160 Biomarkers

Anupam Dey

Abstract Antimicrobial stewardship focusses on interventions to improve and measure the appropriate use of antimicrobial agents. To fight antimicrobial resistance, timely diagnosis of infections, justifiable use of drugs, and avoidance of antimicrobial overprescribing and overuse are of paramount importance. Novel biomarkers aid in this process and are thereby gaining prominence. Biomarkers may be included into clinical guidelines to make their roles clear. This chapter discusses various biomarkers specific to bacterial, viral, and fungal infections which can be used for point of care testing. Biomarker based clinical algorithms prepared using regional data will help in clinical decision-making, thereby aiding rational prescription of antimicrobials.

Introduction scenario were avoidable,2 thus leading to unnecessary expenditure, antibiotic resistance, adverse drug reactions, Antimicrobial stewardship is defined as “coordinated and secondary infections with Clostridium difficile. Rapid interventions designed to improve and measure the biomarker testing is need of the hour. However, till now the appropriate use of antimicrobial agents by promoting rules for integrating biomarkers in antibiotic prescription the selection of the optimal antimicrobial drug regimen decisions are not well known. Defined reference values including dosing, duration of therapy, and route of for bacterial infections are often absent, thus affecting administration.”1 the sensitivity and specificity of biomarkers.3 Use of In the background of increased incidence of biomarkers may be included into clinical guidelines to antimicrobial resistance throughout the world, make their roles clear. This will be particularly helpful in antimicrobial stewardship programs are focusing on the primary care setting where patient turnover is quite timely diagnosis of infections and the justifiable use of high and antibiotic prescription is widespread.4,5 drugs. Frequently, ignorance of the etiology of infection leads to antimicrobial overprescribing and overuse. This diagnostic dilemma may also result in late initiation of Biomarkers antimicrobial therapy and poor outcomes. Recently new The following biomarkers will be discussed further and biomarkers have been used to help making a clinical their use particularly for suspected pneumonia or sepsis diagnosis. Novel biomarkers are an important addition in will be defined: the repertoire of antimicrobial stewardship program, to „„ Bacterial—C-reactive protein (CRP), procalcitonin (PCT) aid in timely diagnosis and appropriate antimicrobial use. „„ Fungal—1,3-beta-D-glucan (BDG), Candida albicans In one estimate from the USA it was observed that germ tube antibody (CAGTA), and Galactomannan close to 50% of antibiotic prescriptions in the outpatient (GM)

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12 „„ Viral markers—Myxovirus resistance protein A (MxA) for diagnosis of sepsis. Serial PCT measurements should „„ Others—Adrenomedullin (ADM), Triggering receptor be taken in sepsis and levels of less than or equal to on myeloid cells 1 (TREM 1), Urinary clusterin, etc. 0.5 µg/L should signal the need for discontinuation of antibiotics. Bacterial Infection Biomarkers From available literature, use of PCT for antibiotic stewardship in respiratory infections (specially LRTI) has C-reactive Protein been found to reduce initial prescription of antibiotics An acute phase reactant that indicates inflammation due by 40–50% in emergency patients and by 70–80% in to multiple causes. Use of CRP in differentiating between ambulatory patients. It has also reduced antibiotic bacterial and viral etiology has been studied widely. It prescription in pneumonia (CAP) by 40–50%.13-15 has been proven that CRP is very sensitive in identifying infections of bacterial etiology and thus helps in taking Fungal Infection Biomarkers decision on instituting antibiotics.6 In a study of patients in Vietnam suffering from acute Detection of invasive candidiasis is challenging. High respiratory tract infections it was found that using CRP cost of new antifungals adds to the problem. Traditional threshold of 20 mg/L in adults, there was reduction of culture methods are unable to detect close to 50% of cases. antibiotic prescription from 78% to 64%. Similarly, in Thus, fungal infection biomarkers may improve patient 16 primary care setting, rapid CRP testing with a threshold outcomes. of 40 mg/L resulted in a significant reduction in antibiotic prescription.7,8 1,3-beta-D-glucan BDG is a component of the cell wall of most fungi Procalcitonin including Candida species. Elevated levels in blood PCT is an amino acid prohormone of calcitonin. On can act as a biomarker to diagnose candidemia or exposure of body to bacterial toxins, serum PCT becomes invasive fungal infection and thus rationalize antifungal detectable in blood. Interferon-gamma released in viral administration. False-positive results can be found with infection downregulates its release. Other inflammatory intravenous immunoglobulin, intravenous albumin, states usually do not affect the serum concentrations certain hemodialysis filters, and with some antibiotics. of PCT. False positive increase of levels have been seen Serial BDG assays have a greater negative predictive value in burns, post-surgery, trauma, and renal dysfunction. thereby guiding discontinuation of empirical antifungal False negative results may occur in too early testing or in therapy. loculated infections.9 Candida Albicans Germ Tube Antibody Role in Respiratory Tract Infections Candida albicans germ tube antibody can be released PCT has been used as a tool to help in diagnosis of bacterial during invasive candidal infection. Its sensitivity and pneumonia when there is clinical dilemma or negative specificity to detect invasive candidiasis has been reported culture results. Serial PCT concentrations have helped as more than 75% and more than 90%, respectively.17 in deciding escalation/de-escalation/discontinuation Although study results are variable, CAGTA with or without of antimicrobial therapy. Various guidelines (Surviving BDG can aid in diagnosis of invasive candidiasis. However, Sepsis guidelines and IDSA) recommend repeating PCT the utility of CAGTA on course of illness is debatable.18 levels serially to decide duration of antibiotic therapy in critically ill patients.10 Standard reference value of PCT in Galactomannan adults is usually 0.15 ng/mL or less. PCT rises within 2–6 Blood assay for GM has improved detection of invasive hours and peaks at 12–24 hours.2,11 aspergillus infection at an early stage, particularly among the immunocompromised. Sensitivity and specificity of Role in Sepsis this marker are more than 70% with cut-off value of 0.5.19 Meta-analyses have established PCT as superior to CRP for The IDSA guidelines recommend use of GM for prompt the diagnosis of sepsis. Levels of 1–2 µg/L are considered diagnosis of invasive aspergillus infection especially in

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patients with hematological malignancy or post-stem cell The ATS/IDSA guidelines endorse the routine use of transplant state.20 MRSA nasal PCR screening for the de-escalation of MRSA coverage. This has been shown to allow a median decrease Viral Infection Biomarkers of 2.1 days of vancomycin therapy.26 Viral (Myxovirus Resistance Protein A) Other Potential Bacterial Biomarkers in Myxovirus resistance protein A is induced by interferons Development and is specifically elevated in patients with viral infections. These are Amyloid A, Liposaccharide binding protein, It has the potential to allow rapid differentiation between Interleukin-10, and nCD64.27 viral and bacterial respiratory infections. In combination with CRP or PCT, elevated levels of MxA can help identify Conclusion patients with likely viral infection, thus helping antibiotic stewardship activities.21 Point-of-care biomarker testing allows rational antimicrobial use. Stewardship programs should analyze regional data of Other Biomarkers local population for using biomarkers in clinical decision- making. More regional studies are required for preparing Adrenomedullin biomarker based clinical algorithms. ADM is a peptide hormone. Its half life is very less; hence pro ADM (cut-off values 3.5–5.5 nmol/L) is often measured References clinically. ADM has been used clinically as a mortality . 1 Society for Healthcare Epidemiology of America, Infectious predictor and prognostic marker in inflammation and Diseases Society of America, Pediatric Infectious Diseases Society. 22 particularly in Community acquired Pneumonia. Policy statement on antimicrobial stewardship by the Society for Increased ADM concentrations will indicate increased Healthcare Epidemiology of America (SHEA), the Infectious Diseases severity and mortality in SIRS and septic shock. Pro-ADM Society of America (IDSA), and the Pediatric Infectious Diseases may be better in this regard. Society (PIDS). Infect Control Hosp Epidemiol. 2012;33(4):322-7. 2. Joseph P, Godofsky E. Outpatient antibiotic stewardship: a growing frontier-combining myxovirus resistance protein a with other Triggering Receptor Expressed on Myeloid Cells 1 biomarkers to improve antibiotic use. Open Forum Infect Dis. TREM 1 is an immunoglobulin expressed on the surface 2018;5(2):ofy024. of macrophages, neutrophils, and monocytes. Phagocytes . 3 Keitel K. Biomarkers to improve rational antibiotic use in low- resource settings. Lancet Glob Health. 2019;7(1):14-5. release soluble TREM 1 (sTREM 1) on stimulation, which . 4 Verbakel JY, Lemiengre MB, De Burghgraeve T, et al. Should all acts as a marker of infection specifically for pneumonia acutely ill children in primary care be tested with point-of-care CRP: 23 and sepsis. Measurement thresholds are 725 pg/mL to a cluster randomised trial. BMC Med. 2016;14(1):131. diagnose sepsis (sensitivity up to 70% and specificity up 5. Mendelson M, Røttingen JA, Gopinathan U, et al. Maximising access to 60%),23 and 5 pg/mL in the diagnosis of pneumonia to achieve appropriate human antimicrobial use in low-income (sensitivity of 98% and specificity of 90%).24 and middle-income countries. Lancet. 2016;387(10014):188-98. . 6 Lubell Y, Blacksell S, Dunachie S, et al. Performance of C-reactive protein and procalcitonin to distinguish viral from bacterial Urinary Clusterin and malarial causes of fever in southeast Asia. BMC Infect Dis. Its use has been studied as a biomarker of nephropathia 2015;15:511. . 7 Do NT, Ta NT, Tran NT, et al. Point-of-care C-reactive protein epidemica (a type of hemorrhagic fever with renal 25 testing to reduce inappropriate use of antibiotics for non-severe syndrome) caused by Puumala virus infection. acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. Lancet Glob Health. 2016;4(9):633-41. Methicillin-resistant Staphylococcus Aureus . 8 Althaus T, Greer RC, Swe MMM, et al. Effect of point-of-care (MRSA) Nasal Screens C-reactive protein testing on antibiotic prescription in febrile patients attending primary care in Thailand and Myanmar: an It can be used in de-escalation of MRSA therapy, mainly open-label, randomised, controlled trial. Lancet Glob Health. in patients with suspected or confirmed pneumonia. 2019;7(1):119-31.

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9. Albrich WC, Harbarth S. Pros and cons of using biomarkers versus Candida colonization and invasive candidiasis in patients with clinical decisions in start and stop decisions for antibiotics in the severe abdominal conditions. Intensive Care Med. 2012;38(8): critical care setting. Intensive Care Med. 2015;41(10):1739-51. 1315-25. 10. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: 19. Leeflang MMG, Debets-Ossenkopp YJ, Wang J, et al. Galactomannan international guidelines for management of sepsis and septic detection for invasive aspergillosis in immunocompromised shock: 2016. Intensive Care Med. 2017;43(3):304-77. patients. Cochrane Database Syst Rev. 2015;2015(12):007394. 11. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic 20. Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice stewardship program: guidelines by the Infectious Diseases guidelines for the diagnosis and management of aspergillosis: 2016 Society of America and the Society for Healthcare Epidemiology of update by the Infectious Diseases Society of America. Clin Infect America. Clin Infect Dis. 2016;62(10):51-77. Dis. 2016;63(4):1-60. 12. Uzzan B, Cohen R, Nicolas P, et al. Procalcitonin as a diagnostic test for 21. Self WH, Rosen J, Sharp SC, et al. Diagnostic accuracy of FebriDx: a sepsis in critically ill adults and after surgery or trauma: a systematic rapid test to detect immune responses to viral and bacterial upper review and meta-analysis. Crit Care Med. 2006;34(7):1996-2003. respiratory infections. J Clin Med. 2017;6(10):94. 13. Briel M, Schuetz P, Mueller B, et al. Procalcitonin-guided antibiotic 22. Lundberg OHM, Bergenzaun L, Ryden J, et al. Adrenomedullin and use vs a standard approach for acute respiratory tract infections in endothelin-1 are associated with myocardial injury and death in primary care. Arch Intern Med. 2008;168(18):2000-7. septic shock patients. Crit Care. 2016;20(178):1-11. 14. Burkhardt O, Ewig S, Haagen U, et al. Procalcitonin guidance and 23. Stover KR, Kenney RM, King ST, et al. Evaluation of the use of reduction of antibiotic use in acute respiratory tract infection. Eur novel biomarkers to augment antimicrobial stewardship program Respir J. 2010;36(3):601-7. activities. Pharmacother. 2018;38(2):271-83. 15. Lieberman D, Shvartzman P, Korsonsky I, et al. Aetiology of 24. Barati M, Bashar FR, Shahrami R, et al. Soluble triggering receptor respiratory tract infections: clinical assessment versus serological expressed on myeloid cells 1 and the diagnosis of sepsis. J Crit Care. tests. Br J Gen Pract. 2001;51(473):998-1000. 2010;25(2):362.e1-6. 16. Clancy CJ, Nguyen MH. Finding the “missing 50%” of invasive 25. Hwang H, Hwang BY, Bueno J, et al. Biomarkers in infectious candidiasis: how nonculture diagnostics will improve understanding diseases. Dis Markers. 2018;2018:8509127. of disease spectrum and transform patient care. Clin Infect Dis. 26. Parente DM, Cunha CB, Mylonakis E, et al. The Clinical utility of 2013;56(9):1284-92. methicillin-resistant Staphylococcus aureus (MRSA) nasal screening 17. Zaragoza R, Peman J, Quindos G, et al. Clinical significance of the to rule out MRSA pneumonia: a diagnostic meta-analysis with detection of Candida albicans germ tube-specific antibodies in antimicrobial stewardship implications. Clin Infect Dis. 2018;67(1): critically ill patients. Clin Micro Infect. 2009;15(6):592-5. 1-7. 18. Leon C, Ruiz-Santana S, Saavedra P, et al. Value of b-D-glucan and 27. Chan T, Gu F. Early diagnosis of sepsis using serum biomarkers. Candida albicans germ tube antibody for discriminating between Expert Rev Mol Diagn. 2011;11(5):487-96.

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Misutilizing Medicine for 161 Biological Warfare

Jayanta Kumar Panda, Biswojit Behera

Abstract Biological Warfare is the intentional use of biological agents to cause morbidity and mortality in humans. The Bioweapons, those used in wars and by terrorist groups are attractive because of their ability to produce wide range of diseases, low production costs, no easy accessibility by routine security systems, and their easy transport from one place to another. In addition, after development of novel technologies that are primarily designed for use in early diagnosis and treatment and decreases the burden of diseases and its consequences on humans health, but this development of medicinal novel technology has often been used in wrong direction to produce more Bioweapons which ultimately threaten the well-being of the whole mankind.

Introduction Biocrime: Biological agent used by a person/group against a person/small group often for revenge or extortion.1 From ancient ages to modern era, history reveals there were multiple number of biological wars among persons, Biological warfare: A state actor uses a biological agent as among states, and among nations to empower over others. part of its armamentarium in waging war.1,5 There was an intention behind use of biological agents like Biological agents: Biological agents (bio-weapons) are microorganisms, and toxins, generally of microbial, plant, living organisms or replicating entities (viruses) that or animal origin to produce not only disease and/or death reproduce or replicate within their host to cause harm.2,3 in humans and damaging live stocks and crops but also to 4 create fear, panic, and paralyze uncertainty. CDC category of biological agents: To protect this there were developments of biodefense „„ Category A: These are high priority agents that easily in the form of biological weapons convention from time to disseminated or transmitted from person to person time, but still there is continuous research on development with high mortality rates. With a potential for major public health impact, might cause public panic and of bio-weapons by the nations. Now for protection against social disruption. biological warfare each nation continued research along „„ Category B: Second highest priority. These are counter measures, including vaccines and antisera. moderately easy to disseminate. They have moderate morbidity rates and low mortality rates. These agents Definitions require specifically enhanced diagnostic capacity. Bioterrorism: It is an action by a non-state actor to achieve „„ Category C: Emerging pathogens that could be a political, ideological, or religious goal. (Desire to engineered for mass dissemination in the future terrorize as much or more than causing casualties.)1,5 because of availability, ease of production, and

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TABLE 1 CDC categories of biological agent

Category A Category B Category C Anthrax (Bacillus anthracis) Psittacosis (Ch. psittaci) (Emerging infections) Botulism (Cl. botulinum toxin) Epsilon toxin of Cl. perfringens Hantavirus Plague (Yersinia pestis) Melioidosis (B. pseudomallei) SARS coronavirus Smallpox (Variola major) Glanders (Burkholderia mallei) Pandemic influenza Tularemia (Francisella tularensis) Food safety threats (e.g., Salmonella spp., E. coli O157; H7, Nipah Shigella) Viral hemorrhagic fevers: Lassa, New World Viral encephalitis [alphaviruses (e.g., Venezuelan, eastern, (Machupo, Junin, Guanarito, Sabia), Crimean and western equine encephalitis)] Congo, Rift Valley, Ebola, Marburg Brucellosis (Brucella spp.) (Coxiella burnetii) Ricin toxin from Ricinus communis (castor beans) Staphylococcal enterotoxin B Water safety threats (e.g., V. cholerae, Cr. parvum)

dissemination and potential for high morbidity and „„ Infectious form: Spores-Hardy, resistant to environ­ mortality rates and major health impact. mental conditions The category and agents are shown in Table 1. „„ Relatively easy to weaponize Example: Anthrax (Bacillus anthracis)6 „„ September 2001, Anthrax used as bio-weapon through „„ The most misused agent in biological warfare US Postal system „„ Rout of transmission: By cutaneous and inhalation „„ 22 cases (18 confirmed)—11 inhalational + 11 „„ Signs and symptoms: cutaneous. —— Prodermal—fever, headache, tiredness „„ 5 deaths (all among inhalational) —— Cutaneous (95%)—pustules, eschar (Figs. 1A to C) „„ Ames strain used (beta lactamase + cephalosporinase), —— Pulmonary (5%)—cough, chest pain, dyspnea but luckily susceptible to antibiotics Diagnosis: „„ Maximum amount of spore in a letter—2 g (100 billion „„ Skin biopsy for cutaneous lesions to 1 trillion spores) (LD 50 = 10,000) „„ Blood culture 7 „„ ELISA, PCR Plague (Yersinia pestis) „„ Chest X-ray- widened mediastinum (Hilar and Highly contagious. Pneumonic plague is most severe. mediastinal lymphadenopathy) with or without infiltrate and pleural effusion (Figs. 2A and B) Signs and symptoms: „„ Pneumonic plague: Due to inhalational exposure. Treatment: Cough with blood tinged sputum. „„ Ciprofloxacin, Penicillin, Doxycycline „„ Bubonic plague: Due to infection through skin causes „„ Treated for 60 days ulcers (Fig. 3), Fever, Chills, Nausea, Vomiting, Buboes Prevention: (Fig. 3) (1–8 days). „„ Vaccination—6 doses over 18 months, booster annually „„ Septicemic plague: Usually from bubonic plague fever, „„ Chemoprophylaxis—Cipro/Doxy 4 weeks before chills, nausea, vomiting, bleeding in skin, ischemia in exposure limbs.

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A B

C Figs. 1A to C: Skin lesions in anthrax

A B Figs. 2A and B: X-ray findings in anthrax

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Fig. 3: Skin lesions in plague Fig. 4: Eruptions in small pox

Diagnosis: „„ Fever, malaise, headache, backache, emesis, „„ Clinical features: Microscopic examination of bubo maculopapular to vesicular to pustular skin lesions. fluid/sputum Centrifugal, same stage of development, hemorrhagic „„ Cultures and PCR/DFA and malignant forms (5–10%) (Fig. 4)

Treatment: Diagnosis: „„ Culture, PCR, Electron Microscopy „„ Gentamicin, Streptomycin, Doxycycline Prevention: Treatment: „„ „„ Formalin fixed vaccine, Flea control measures Supportive treatment—Cidofovir, Anti-vaccinia immunoglobulin Spread: „„ Through bite of infected fleas Prevention: „„ Through droplet spread from pneumonic plague „„ Vaccinia immunization patients „„ Weaponization—Infected fomites (historical use), „„ Through direct contact with non-intact skin Aerosol sprays Weapon potential: 9 „„ Labile in environment (1 hour) Tularemia (Francisella tularensis) „„ Highly contagious, person to person spread „„ Extremely infectious (10–50 by inhalation) „„ Can be weaponized as aerosols (10 km) „„ Infection through non intact skin, mucous membrane, GI tract, Respiratory tract Smallpox (Variola) „„ Vactors: Rabbits, ticks, water rats, deer. By 1980, close to whole world population was immune Signs and symptoms: and not important as bio-weapon then. Now susceptible „„ Incubation periods 1–14 days population (50%). „„ Ulceroglandular (75%) (Figs. 5 and 6) and Typhoidal High infectivity, can spread at a factor of 10–20 (25%) Between 10–30% mortality in untreated „„ Fever, chills, malaise, myalgia, headache, chest Signs and symptoms: discomfort, dyspnea, skin rash, pharyngitis, „„ Incubation period: Between 7–17 days (12–14) conjunctivitis Hilar adenopathy on chest X-ray

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A B Figs. 5A and B: Skin lesions in tularemia

„„ Bunyaviridae: Crimean Congo, Rift Valley „„ Filoviridae: Ebola, Marburg Transmission: „„ Person-to-person transmission through direct contact with body fluids (Lassa, Ebola, Marburg) „„ Aerosol sprays infectious (animal studies) „„ Up to 90% mortality Signs and symptoms: „„ Fever, myalgia, prostration, and DIC with thrombocytopenia and capillary hemorrhage „„ Maculopapular or erythematous rashes „„ Leukopenia, temperature-pulse dissociation, renal failure, and seizures Diagnosis should be suspected in anyone with Fig. 6: Glandular lesion in tularemia temperature >38.3°C for <3 weeks who also exhibits at least two of the following: hemorrhagic or purpuric rash, Diagnosis: epistaxis, hematemesis, hemoptysis, or hematochezia in „„ Gram stain, culture (blood, ulcer discharge, sputum), the absence of any other identifiable cause. immunohistochemistry, PCR Diagnosis: Treatment: „„ RT-PCR, Antigen isolation „„ Streptomycin, Gentamicin, Doxycycline, Ciprofloxacin Treatment: Prevention: „„ Supportive therapy: Ribavirin, IFα, Hyperimmune Ig „„ Chemoprophylaxis: Doxycycline, 100 mg PO bid × 14 Prevention: days or Ciprofloxacin, 500 mg PO bid × 14 days „„ No known chemoprophylaxis, no vaccines „„ Weaponization—Aerosol sprays „„ Strict isolation and PPE (N95 mask or PAPR)

Hemorrhagic Fever Viruses Botulinum Toxin (Clostridium botulinum)8 „„ Arenaviridae: Lassa, New World (Machupo, Junin, „„ One of the most potent toxins. Produced by Clostridium Guanarito, and Sabia) botulinum

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„„ Toxin is labile in atmosphere (1% per min), Organism Treatment: is easily destroyed (chlorine, heat) „„ Fluid and electrolyte replacement „„ Botulism can occur: infection in a wound or the „„ Antibiotics—Doxycycline, Ciprofloxacin, Erythromycin intestine, the ingestion of contaminated food, or the inhalation of aerosolized toxin Prevention: „„ Live vaccine—50% efficacy, 2 doses + booster Signs and symptoms: „„ Inactivated vaccine—rapid protection, 2 doses, 85% „„ Incubation period: 12–72 hours efficacy, 2–3 years „„ Dry mouth, blurred vision, ptosis, weakness, dysarthria, dysphagia, dizziness, respiratory failure, progressive Spread: paralysis, dilated pupils „„ By contamination of drinking water supply. Easily destroyed by heat, boiling, chemical disinfectants. Diagnosis: „„ Mouse bioassay and toxin immunoassay Corona Viruses Treatment: They are mostly contagious in nature mainly causing three „„ Supportive—Intubation, mechanical ventilation, TPN dangerous diseases: SARS, MERS, COVID-19. „„ Equine antitoxin (only against A & B) Severe Acute Respiratory Syndrome (SARS) Prevention: „„ Botulinum toxoid is available for high-risk workers, lab Caused by SARS-CoV corona virus. workers, military personnel. In November 2002, it started from Guangdong province of Southern China, eventually reaching Hong Kong. From Examples of use: Botulinum toxin was the primary focus there it rapidly spread, causing infections in more than 24 of the pre-1991 Iraqi bio-weapons program. (19000 l conc. countries. toxin.), Aum Shrinrikyo cult unsuccessfully attempted on Spreads—by aerosols a least three occasions to disperse botulism toxin into the civilian population of Tokyo. Signs and symptoms: „„ Begins over 7 days 1990—Outfitted a car to disperse botulinum toxin through „„ Dry cough, chills, diarrhea, breathlessness, body ache, an exhaust system and drove the car around Parliament. pneumonia 1993—Attempted to disrupt the wedding of Prince „„ Mortality rate of 9.6% Naruhito by spreading botulinum in Tokyo via car. 1995—Planted three briefcases designed to release Diagnosis: botulinum in a Tokyo subway. „„ RTPCR, cell culture Treatment: Cholera (Vibrio Cholera) „„ Supportive—Corticosteroids, oxygenation, ribavirin,

„„ Causes acute, potentially severe gastroenteritis lopinavir and ritonavir, ET tube intubation „„ „„ Spread through contaminated drinking water Prevention—Hand washing, PPE wearing, using face mask (N95, 3-layered surgical) Signs and symptoms: „„ Begins in 12–72 hours Middle East Respiratory Syndrome (MERS) 10 „„ Watery rice water diarrhea, abdominal pain, cramps, dehydration, electrolyte imbalance, seizures and Caused by MERS-CoV corona virus cardiovascular collapse in children First recognized by scientist in Saudi Arabia after severe respiratory illness. Since then it has spread to other Diagnosis: countries „„ Stool microscopy—dark field Spread by—Aerosols

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Fig. 7: Weapons development cycle

Signs and symptoms: Diagnosis: „„ Fever, cough, breathlessness „„ Rapid antigen test, RTPCR „„ Mortality rate—35.2% Treatment: Diagnosis: „„ Supportive—Azithromycin, doxycycline, ivermectin, „„ RTPCR HCQs, favipiravir, remdesivir, corticosteroids, LMWH, ET tube intubation Treatment: „„ Supportive—ET tube intubation, NSAIDs, oxygenation Prevention: „„ Hand washing, PPE wearing, using face mask (N95, Prevention: 3-layered surgical) „„ Hand washing, PPE wearing, using face mask (N95, „„ Weaponization—It is the process of converting the 3-layered surgical) biological agent into a usable weapon. „„ No vaccine available „„ Delivery device—Bombs, Missiles, Spray systems – Aerial, Aerosol based. COVID-19 10 „„ Non-traditional—Food, water supplies, animals, In December 2019, CDC started monitoring the outbreak insects. of a new corona virus named SARS-CoV-2, which started from Wuhan city of China and then spread to nearly every Treaties and Conventions country leading the WHO to declare a pandemic. Geneva protocol,5,13 1925: Geneva Protocol for the Spreads by—Aerosols prohibition of the Use in War of Asphyxiating, Poisonous Signs and symptoms: or Other Gases and of Bacteriological Methods of Warfare th „„ Fever, cough, breathlessness, loose motion, loss of was adopted by international community on 17 June, taste and smell, body ache, chest pain 1925. It banned the use but didn’t proscribe the research, „„ Mortality rate—Varies among countries production, or possession. It was appeal by international „„ 6% in the US Red Cross and Poland. It was customary international law. „„ 3% in India A no first use agreement only.

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Biological weapons convention5,13 1972: Eighteen-Nation Biological warfare with India:11,12 Disarmament Committee in 1969. Convention on „„ Nodal agencies—DRDO (MoD), NDMA, MoHA, the prohibition of the development, production, and MoHFW stockpiling of bacteriological and toxin weapons and on „„ Indian Biodefence Program—started in 1973 their destruction was signed on 10th April 1972. Entered into force in 1975. First treaty to ban an entire class of Conclusion weapons doesn’t address non-state actors, e.g., terrorists. No protocol to monitor compliance (Fig. 7). Time and again Medicine has been misutilized for biological warfare to satisfy human ego and the desire to harm the mass by the knowledge and the commodities of healing. We Prevention Against Biological Warfare misutilize our discoveries to injure and kill innocent people in the name of war instead of fighting against the microbe to It is necessary to be aware of common epidemiological prevent the diseases and save the suffering mass. The recent clue for detecting early of a biological attack. pandemic of COVID-19 has originated at Wuhan state of China „„ At particular time there is a single cause of certain from a virology lab with similar attempts and the whole world has suffered for a year and we don’t know what is there in disease of unknown cause in a large area which may future. At least now the pandemic should open the vision of not have epidemiological explanation. our world leaders to resolve to stop such heinous suicidal act „„ Genetically engineered agent. for the benefit of everyone. „„ High morbidity and mortality rates with the same or similar symptoms. References „„ In a particular geographical or seasonal distribution. . 1 Jansen HJ, Breeveld FJ, Stinjnis C, et al. Biological warfare, „„ Transmission through aerosols, food, water. bioterrorism, and biocrime. Clin Microbial Infect. 2014;20(6):488-96. „„ Rare illness affecting large population or certain age 2. Pohanka M, Kuca K. Biological warfare agents. EXS. 2010;100:559-78. group; with unusual trends of mortality and morbidity. . 3 Kerwat K, Becker S, Wulf H, et al. Biological weapons. Dtsch Med Wochenschr. 2010;135(33):1612-6. „„ Clustering of cases for treatment. . 4 CDC Bioterrorism Agents/Diseases (by category). 2018. Available from http://emergency.cdc.gov/agent/agentlist-category.asp Primary Prevention . 5 Dasilva EJ. Biological warfare, bioterrorism, biodefence and the biological and toxin weapons convention. EJB. 1999;2(3):99-129. By creating a strong global norm that rejects development 6. Datta KK, Jagvir S. Anthrax. Indian J Pediatr. 2002;69(1):49-56. of such biological weapons. . 7 Yang R. Plague: recognition, treatment, and prevention. J Clin Microbial. 2017;56(1):e01519-17. 8. Sotos JG. Botulinum toxin in biowarfare. JAMA. 2001;285(21):2716. Secondary Prevention . 9 Cronquist SD. Tularemia: the disease and the weapon. Dermatol Clin. 2004;22(3):313-20. Early detection and prompt treatment of disease. There 10. Wang HJ, Du SH, Yue X, et al. Review and prospect of pathological is important role of medical community by participating features of corona virus disease. Fa Yi Xue Za Zhi. 2020;36(1):16-20. in disease surveillance and reporting, and thus providing 11. Riedel S. Biological warfare and bioterrorism: a historical review. BUMC Proceedings. 2004;17(4):400-6. the first indication of biological weapons use. In addition, 12. Christopher GW, Cieslak TJ, Pavlin JA, et al. Biological warfare. A continued research to improved diagnostic capabilities, historical perspective. JAMA. 1997;278(5):412-7. therapeutic agents, and effective response plans14,15 will 13. Berdal BP, Omland T. Biological weapons conventions and history. further strengthen secondary prevention measures. Tidsskr Nor Laegeforen. 1990;110(6):736-40. 14. Kumar H, Rani R. Development of biosensors for the detection of biological warfare agents: its issues and challenges. Sci Prog. Tertiary Prevention 2013;96(3):294-308. 15. Spencer RC, Lightfoot NF. Preparedness and response to Prevention of disability from disease. bioterrorism. J Infect. 2001;43(2):104-10.

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Antimicrobial Resistance: 162 Is It Worrisome?

Ritu Karoli

Abstract Antimicrobial resistance (AMR) is said to occur when microbes are protected from effects of antimicrobial agents by evolving genetic or acquired mechanisms. Rising AMR is a global threat to public health across the globe. There are various causes of AMR in community, health-care system, and agriculture industry. The need of the hour is to identify and remove these causes, prevent the misuse of antimicrobial agents by antibiotic stewardship, and apply the knowledge of novel research and technology to address this growing menace.

“There is probably no chemotherapeutic drug to which in origin. Coordinated action is required to minimize the suitable circumstances the bacteria cannot react by in some emergence and spread of AMR. way acquiring ‘fastness’ [resistance].” Antimicrobials have made the management of –Alexander Fleming, 1946 infectious diseases easier thereby decreasing morbidity and mortality. If current trends continue, it is projected Introduction that, by 2050, AMR could result in over 10 million deaths per year and over 100 trillion USD in lost output globally.1 The discovery of antibiotics was an important landmark World Health Organization (WHO) is coordinating a global in the history of medicine that revolutionized treatment campaign to raise awareness of antibiotic resistance and and saved countless lives. Antibiotics are one of the encourage best practices among the public, policymakers, most commonly prescribed drugs in clinical practice. health and agriculture professionals, to avoid further Unfortunately, resistant strains of microbes have religiously emergence and spread of antibiotic resistance.2 followed the path of these “magic bullets” antimicrobial resistance (AMR) is the ability of microorganisms such as bacteria, fungi, or protozoans to grow despite exposure What is Superbug? to antimicrobial substances designed to inhibit their There has been emergence of microbes which are resistant growth. Reduction in or loss of an agent’s antibacterial to multiple antimicrobials are called as superbugs. effect is referred to as resistance, and the properties of They cause difficult to treat life threatening infections or alterations in the bacterium that result in reduced and require higher doses of antimicrobials along with antimicrobial activity are termed resistance mechanisms. alternative or adjuvant medications. They increase rate AMR is one of the biggest public health problems of recent of hospitalization, duration of stay at hospital, and lead decades that poses significant challenge to prevention and to economic burden on society and health-care system. treatment of various infections. It is a complex issue that Many of them are multidrug resistant infections such as affects different sectors of society and is multifactorial in Mycobacterium tuberculosis, Acinetobacter, Enterobacter

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spp., Enterococcus, Escherichia coli, Pseudomonas, and Flowchart 1: Environmental factors of MDR Staphylococcus aureus. These infections are caused by a (multidrug resistant strains) range of opportunistic pathogens (organisms that only cause disease in immunocompromised individuals). Device-associated infections, ventilator-associated pneumonia (VAP), and urinary tract infections (UTI) account for approximately 60% of all hospital-associated infections. Causes of AMR „„ Community— —— Overuse of antibiotics—Over the counter availability of antibiotics in absence of valid prescription by a qualified medical professional —— Inappropriate use/misuse of antibiotics —— Inappropriate choices because of diagnostic inaccuracy Exposure to antibacterial agents results in the —— Inadequate dosing/timing and noncompliance selection of resistant strains within an otherwise —— Self-medication susceptible bacterial population. „„ Hospital-acquired infections— Mechanisms of resistance—Microbes have outstanding —— Intensive and unjustified/irrational use of quality to survive among variety of environmental antimicrobial drugs adversities. Plasmids are extrachromosomal DNA, mostly —— Emergence and spread of multidrug resistant present in bacteria. They replicate autonomously. The nosocomial infections size varies from a few base pairs to thousands base pairs. —— Immunocompromised patients Many antibiotic resistance genes are present in plasmids. —— Prolonged stay in hospitals/intensive care units, It is common that resistant bacteria have combinations treatment of immunocompromized patients of resistance mechanisms3 either within one category or —— Failure to implement effective infection control among categories, and many plasmids contain more than measures one resistance gene. Thus, plasmid acquisition itself can —— Absence of antimicrobial stewardship programs in many cases confer resistance to multiple antibacterial „„ Environmental causes of AMR (as shown in agents. Flowchart 1) Mechanisms of resistance have been shown in Figure 1. —— Overwhelming use of antibiotics in animal „„ Reduced penetration and permeability and increased husbandry and agriculture. This results in the efflux pumps—Some bacterial species are intrinsically evolution of multidrug-resistant organisms that resistant to certain group of antibiotics because of act as reservoirs. These organisms or their genes reduced penetration and permeability of cell membrane can spread to humans either through direct and increased efflux pumps. TetA efflux pumps contact or through the environment. specifically pump tetracycline out of the cell. Mutations —— Organic pesticides used in agriculture may persist in Porin (protein channels present incell membrane) in the soil. lead to porin los or change in size and conductance or —— Sewage-water contamination with soil and decrease in expression results in less concentration of environment. antibiotic in the cell and can lead to AMR. —— The excessive use of antiseptics and biocides leads „„ Enzyme inactivation and chemical modification— to resistance against these compounds and cross- Enzymes produced by certain bacteria inactivate the resistance to antibiotics. target site, such as β lactamase enzyme, which prevent —— Many antibacterial drugs are derived from natural β lactam to bind to target site. Another mechanism products of environmental microbial species. mediated by bacteria in which they acquire an

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Fig. 1: Mechanism of antibiotic resistance

enzyme that chemically modify the target of the „„ Economic burden on patient and health-care system. antibiotics. Ribosomal methylation of erythromycin „„ Infections caused by multidrug-resistant bacterial makes it ineffective and N Acetyltransferase modifies strains lead to increased societal costs in terms of aminoglycosides. mortality and loss of productivity. „„ Modification of antibiotic target site—Mutations in the bacterial genes, which encode for the protein that 4 is target of an antibiotic. Resistance to penicillin in Antimicrobial Stewardship streptococcus species is due to acquisition of mutation “Using the right antibiotic at the right time at the right dose in penicillin binding proteins. for right duration.” „„ Overproduction/replacement of target site— Goal of antimicrobial stewardship to optimize clinical Sometimes there is overproduction of target sites by outcome while minimizing toxicity and emergence replication of bacteria, which is found in combination of resistance. Antimicrobial stewardship programs with mutation that lowers the ability of antibiotics to are the need of the hour to limit indiscriminant use bind to bacteria, e.g., trimethoprim resistance in E. of antimicrobials. These programs require leadership coli. Some of mutations cause replacement of target commitment, accountability, and drug expertise. They site of bacteria for a particular antibiotic and result in include systemic evaluation of ongoing treatment, resistance. S. aureus is resistant to most of the β lactam tracking and monitoring of antibiotic prescription and antibiotics. resistance pattern and education to clinicians about AMR and optimum prescription. Implications of AMR Antimicrobial stewardship programs are typically Management of critically ill, cancer chemotherapy, organ multidisciplinary and often include infectious disease transplantation, orthopedic surgery, intensive care for physicians, pharmacists, pharmacologist, clinical preterm newborns are being affected. microbiologists, administrators, and epidemiologists. It is

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for practice of promoting the selection of the appropriate Conclusion drug, dosage, route, and duration of antimicrobial therapy. AMR is increasing due to overuse and misuse of antibiotics in human beings and animals. There should be societal Solutions to Combat Antibiotic Resistance commitment to fight against AMR. Health-care professionals AMR is a major concern globally. Infections due to drug- should demonstrate dedication and accountability to optimize resistant pathogens are becoming difficult and a challenge antibiotic prescriptions and patient safety. to treat. Following strategies can be adopted: „„ Mitigation of emergence of MDR strains and prevent spread References „„ Strengthen National one health surveillance program 1. World Health Organization Antimicrobial Resistance: Global Report „„ Rapid and innovative diagnostic facilities to be made on Surveillance 2014. Geneva, Switzerland: WHO; 2014. Available available from https://www.who.int/antimicrobial-resistance/publications/ surveillancereport/en/ „„ Antibiotic stewardship programs should be mandatory . 2 Centers for Disease Control and Prevention, US Department of in health-care systems Health and Human Services. Antibiotic resistance threats in the „„ Accelerate applied and basic research to develop new United States. Atlanta: CDC; 2013. Available from http://www.cdc. antibiotics and new treatment options gov/drugresistance/pdf/ar-threats-2013-508.pdf . 3 Jose M. Munita JM, Aria CA. Mechanisms of antibiotic resistance. „„ Capacity building across the globe by improving Microbiol Spectr. 2016;4(2). international collaborations to prevent AMR . 4 Barlam TF, Cosgrove SE, Abbo LM, et al. Executive summary: „„ Novel therapeutic options can be explored such as implementing an antibiotic stewardship program: guidelines by the antimicrobial peptides, biologics, nanoparticles, infectious diseases society of America and the Society for Healthcare polymer-controlled delivery Epidemiology of America. Clin Infect Dis. 2016;62(10):1197-202.

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163 Chikungunya Arthropathy

Liyakat Ali Gauri, Somya Goyal, Asim Khan, Nadeem Liyakat, Qadir Fatima

Abstract Chikungunya is a vector born disease transmitted to humans by the bite of infected female Aedes aegypti or Aedes albopictus. It causes a multisystem disorder with predominant involvement of musculoskeletal system. Chikungunya arthropathy can develop into chronic phase which may lead to disability and debilitating joint pain. Current treatment options include NSAIDs, Opioids, Anticonvulsants/Antidepressants, Colchicine, DMARDs, Methotrexate. Biologicals, Ultrasound, and Transcutaneous Electrical Current Stimulation have shown promising results. Newer researches are undergoing to provide evidence-based therapeutic options.

Introduction The word chikungunya, in Makonda language, means “that which bends up” or “to become contorted.” It refers to the prostrated appearance of affected patients.1 Chikungunya virus (Fig. 1) is an alpha virus belonging to Togaviridae family. ChikV was first isolated in 1953, in Newala District, Tanzania. The vector-borne disease is transmitted to humans by the bite of infected female Aedes aegypti (tropics) or Aedes albopictus (temperate).2 Clinical Features ChikV is a multisystem disorder with a predominant involvement of musculoskeletal system. Incubation period is 5–7 days:1 „„ Neurological manifestations are meningoencephalitis, Fig. 1: Aedes albopictus or Asian tiger mosquito myelitis, peripheral neuropathy, Guillain-Barré syndrome (GBS). „„ Ophthalmology-keratitis, episcleritis, optic neuritis, „„ Sepsis and septic shock uveitis, and renal detachment. „„ Renal failure „„ Cardiac—uncommon, but serious arrhythmias, „„ Toxic hepatitis vasculopathy, myocarditis, pericarditis, or dilated „„ Pneumonitis 1 3 cardiomyopathy „„ Bullous dermatosis, alopecia

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Mother-to-child Transmission Risk Factors for Developing Chronicity A study of pregnant women concluded in Reunion Island, „„ Comorbidities: RA, diabetes mellitus 2005–2006 epidemic showed that vertical transmission „„ Age more than 45 years 9 rate was 50% when ChikV infection occurred during „„ High viral load (>10 /mL) during acute phase intrapartum period (2 days either side of deliver). Cesarean „„ In a study involving 140 patients with ChikV, smoking, section did not prevent this transmission.4 and female gender were identified as main risk factors for severe joint pain in acute disease as well as Chikungunya Arthropathy chronicity as similar to RA Clinical manifestations can be divided into: „„ Genetic predisposition „„ Acute phase (<3 months) „„ Viral persistence 6,10 „„ Chronic phase (>3 months) „„ Auto immune diseases Acute phase is further divided into viremic (5–10 days ) and subacute post-viraemic phase (6–21 days). Immunopathogenesis of Viremic phase is characterized by sudden onset high Chikungunya Arthropathy grade fever, severe polyarthralgia, myalgia, conjunctivitis, 5 The mechanism of chikungunya arthropathy is unclearly exanthema. understood. Subacute phase is in which fever settles but articular symptoms persists. In acute phase, there is an intense viremia, There is symmetrical, peripheral polyarthralgia which is associated with activation of Type I IFN & involving small, medium, and large joints, which tends IL-6. Proinflammatory cytokines and chemokines are to be more intense in morning and worsens with physical activated. activity.6 This strong immune response clears the virus by CD+4 T cells, NK cells and macrophages and within 7–10 days of Chronic Phase acute infection virus levels become undetectable. For this reason, ChikV PCR for diagnosis after 7 days is Prevalence of ChikV arthritis progressing to chronicity is not useful.2 4.1–78.6%. This phase is similar to rheumatoid arthritis Il-17 is also implicated in chronic joint disease, (RA), spondyloarthritis.7 Various joints are involved in which upregulates IL-1,6, TNF alpha, RANK-L. RANK-L chikungunya. There have been many studies studying osteoprotegerin ratio is disturbed, which further increases involvement of joints (Fig. 2). bone erosions. Whether ChikV persists in synovial tissue Chikungunya has been reported with changes similar in chronic phase is unclear.1 to rheumatoid arthritis. Similar case was reported by jose Sixteen patients from Reunion Island epidemic were kennedy Amaral (Fig. 3).16 Study from Colombia reported studied for persistent viral infection by synovial fluid 25% patients remained symptomatic for joint pain after 20 RTPCR in 10 patients and tissue biopsy in 6 patients. All months follow-up. samples were negative suggesting viral replication is not Similar findings were reported in a meta analysis, the cause of chronic articular disease.11 chronic inflammatory rheumatism (CIR) was present in In a study conducted by Dr Chang on 38 patients 25% cases and chronic arthritis in 14%.8 during 2014–2015 Colombian epidemic, no evidence of In study involving 121 patients from Martinique Island viral persistence was found by synovial fluid RTPCR, mass in Caribbean, 21% patients progressed to seronegative RA spectrometry, and viral culture.8 in 1 year, 37% had flare of underlying degenerative arthritis, 35% had relapse of previous inactive spondyloarthritis and 7% had fibromyalgia.9 Diagnosis An observational study from Kerala found 57% patients „„ Clinical: ChikV should be suspected in endemic had chronic polyarthralgia, 19.5% chronic tenosynovitis areas or in travelers from affected areas or in patients after 15 months of ChikV.1 presenting with high grade fever and joint pain

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Fig. 2: Joints involved in chikungunya as observed in various studies3

Fig. 3: A 50-year-old woman with CCA and synovitis of right 3rd PIP and left 2nd PIP joints. She had acute Chik F 3 years prior and subsequently developed CCA

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A B Figs. 4A and B: Coronal magnetic resonance (MR) T1 image (A) reveals extensive intermediate-signal-causing carpal styloid erosions (arrow), similar to those of rheumatoid arthritis. Axial MRT2 image (B) reveals small fluid collections in the wrist (arrows)

„„ Complete blood count: Anemia, leukopenia, lympho­ symptoms in subacute phase and chronic phase. penia, mild thrombocytopenia Maximum dose of steroids recommended is 0.5 mg/kg. „„ Biochemistry: Increase in liver enzymes and serum Use is not advised in acute phase. creatinine levels In an uncontrolled case series during 2005–2006 „„ RT-PCR: Sensitive from 0 to 7 days after which it is Indian Ocean pandemic, short-term corticosteroids unreliable showed improvement in arthritis and tenosynovitis and „„ IgM ChikV: Detectable in 5–10 days after onset of decreased disability in patients with CCA.1 infection, maximally positive after 3 weeks. May Long-term use is discouraged due to side effects. remain positive up to 2–3 months „„ IgG: Positive after first week of infection and remain Opioids positive for years Weak opioids like codeine and tramadol can be used as As a general rule, serological markers (IgM & IgG) adjunctive. should not be checked in first week of infection: „„ RA factor, anti CCP antibodies, HLA B27, ANA in chronic arthritis Anticonvulsants/Antidepressants „„ MRI—greater sensitivity. Can show synovial thickening, Pregabalin, amitriptyline, and gabapentin can be used for bone marrow edema, effusions, tenosynovitis (Fig. 4).24 peripheral neuropathy and intractable pain.

Treatment Colchicine Study by Rendel showed that colchicine used at 0.6 mg/kg/ NSAIDs day in a patient with persistent ankle and wrist arthralgia PCM remains the initial choice for fever and arthralgia. showed significant improvement.12 NSAIDs should be avoided until dengue has been ruled After 2–3 days, there was resolution of swelling and out as dengue can be complicated by hemorrhage. improvement in joint pain. After 2 months, symptoms were resolved. Corticosteroids Patient continued treatment for 6 months with no Low dose prednisone starting at 5–10 mg OD followed by adverse effects. Study suggested colchicine as a treatment gradual tapering over weeks can be used for intractable option.12

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DMARDs Pandya treated 149 patients with MTX 15–20 mg weekly with HCQ. At 16 weeks, ACR20 was seen in 48.9%, Study on 50 chikungunya patients by Gauri LA et al. shows ACR50 in 18.8%, ACR70 in 4% patients. One patient that chikungunya patients who had persistent arthralgia achieved clinical remission (DAS28-ESR <2.6) and 4/149 on 5-year follow-up mimicked rheumatological disorder showed good clinical response (DAS28-ESR <3.2).18 Like rheumatoid arthritis in 70.58% cases. Therefore, disease-modifying anti-rheumatic drugs (DMARDs) can 13 Biologicals be effective. No human trial to evaluate the efficacy. Methotrexate (MTX) Bouqillard & Combe treated patients of acute Chik developing CIR, with TNF alpha inhibitors. These patients In a study from Reunion islands by Javelle et al. on a patient were refractory to initial MTX therapy. All Patients had with post-chikungunya CIR with 21 months follow-up, good clinical response.15 15 mg weekly MTX lead to clinical improvement in 75% (54/72) patients and 8%(6/72) achieved partial recovery while 9% (7/72) had radiographic worsening of joints. Ultrasound and Transcutaneous Electrical Remaining had to stop MTX due to side effects.14 Current Stimulation In another small study, MTX given to patients with Ribeiro et al. reported the efficacy of ten sessions of poor response to HCQ and SSZ combination therapy led continuous ultrasound with 1 MHZ OD applied from to improvement in 93% cases after 3 months. Only 7% were Monday to Friday followed by infrared laser at dose of 4J & symptomatic at the end of 2 years. 3S per hour. TENS burst with a pulse width of 250US and Bouqillard & Combe treated 19 patients with acute frequency of 2 HZ. chikungunya with MTX, 13 patients (68.4%) had good This association showed post-intervention clinical response.15 improvement in quality of life, which was assessed by SF36 (medical outcome study 36) and VAS.19 Combination DMARD Therapy Ultrasound transmits heat by convection causing Amaral et al. treated 48 CCA patients with 7.5 mg weekly vasodilation and increased blood flow, hence increasing metabolic rate of the cell. MTX with dose escalations for refractory symptoms at 4 TENS stimulates large afferent sensory fibers that block weeks. Final MTX dose was 9.2+3.2 mg/week. first degree nociceptive fibers by releasing endorphins. MTX was combined with oral prednisone at 9 weeks Laser therapy causes photochemical reactions with 6.1+2.2 mg for 9 patients (18%). Two patients within cells, increasing mitochondrial function and ATP received 400 mg daily HCQ with MTX and one received productions, cell proliferation, and accentuating the SSz 1,000 mg. Pain VAS score decreased to 3.0 & 2.6 at the healing process. end of 4 & 8 weeks respectively from a baseline value of 7.7+2.0.16 An open label study by Ravindran & Alias randomized When to Give? What to Give? patients on HCQ who had persistent arthritis (>1 year) Based on French, Brazilian, and WHO guidelines as well patients were divided into two groups: as the studies conducted in India, we can follow these points:20,21 Group A: Received fixed dose combination (MTX 15 mg weekly + SSz 1,000 mg OD + HCQ 400 mg daily. Acute Phase Group B: Continued to take HCQ 400 mg OD. Acute viremic phase (see Flowchart 1): Both groups also took prednisolone for 6 weeks. „„ Supportive care, hydration At 25 weeks, combination therapy showed significant „„ WHO recommend home treatment for non- improvement in both disease activity & disability. VAS complicated acute cases score was significantly less in combination therapy „„ Common analgesics, weak opioids should be used 17 group. „„ NSAIDs to be avoided until dengue has been ruled out

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Flowchart 1: Treatment algorithm for patients presenting in acute phase of chikungunya arthropathy2

„„ Guidelines do not recommend use of steroids during „„ SSZ 2–3 g/day with or without MTX. SSZ should acute viremic phase especially be used in failure or contraindications to „„ Use of heat generating rehabilitative procedures MTX should be avoided in acute phase „„ Biological therapy (particularly TNF alpha) may be used after rheumatological evaluation or in Subacute phase (see Flowchart 2): patients refractory to treatment of corticosteroids or „„ NSAIDs, opioids, or adjunctive treatment for pain DMARDs management „„ A dictum is—“if it looks like RA, treat like RA” should „„ Anticonvulsant/antidepressants like pregabalin and be followed amitriptyline in cases refractory to opioids, NSAIDs. Rehabilitation intervention in all phases of ChikV is „„ Use of prednisolone at 5–20 mg/day with gradual recommended as a complementary non-pharmacological tapering measurement. „„ WHO guidelines support use of HCQ 200 mg OD or CQ 300 mg Od for 4 weeks for resistant symptoms Newer Therapeutic Approach Chronic phase (see Flowchart 3): „„ Analgesics Ribavirin „„ Weak opioids In studies by Ravindran et al., Ribavirin was used in a group „„ NSAIDs of patient with chronic ChikV, analgesics discontinued, „„ Oral corticosteroids may be used at 5–20 mg/day with and Ribavirin started at 200 mg BD for 7 days. All patients gradual tapering reported improvement in pain.6 „„ HCQ with or without MTX or sulfasalazine (SSZ) Favipravir, Ribavirin with a combination of IFN alpha, „„ Corticosteroid dependent disease—use of MTX at umifenovir (antiviral) and Suremein (anti-protozoal) have 10–25 mg/weekly is recommended shown some benefit.2

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Flowchart 2: Treatment algorithm for patients presenting in subacute phase of chikungunya arthropathy2

Flowchart 3: Treatment algorithm for patients presenting in chronic phase of chikungunya arthropathy2

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Abatacept Prophylaxis with MDEF201 T-cell costimulation blocker. In mouse models has shown It is an adenovirus vectored IFN alpha. a significant decrease in periarticular swelling and Studies have shown decreased cytokines and proinflammatory cytokines.2 decreased footpad swelling in mice treated with intranasal MDEF 201. Pentosan Polysulfate Prophylaxis with MDEF201 may have clinical potential NOVEL glycosaminoglycan like molecule developed in endemic areas of ChikV. Especially during outbreaks, it for the treatment of alpha virus infection. Treatment would be useful as a single prophylactic agent that could 23 of ChikV infected mice reduced cartilage thinning and protect over several weeks to those at high risk. immunological infiltration of joints. Intra-articilar levels of proinflammatory cytokines Vaccine

were decreased and anti-inflammatory IL-10 increased „„ Recombinant measles and chikungunya vaccine (MV- 1 through unclear mechanism. Chik) „„ Virus like particle (VLP) vaccine Fingolimod Vaccines induce neutralizing antibodies against E1 Sphingosine-1-phosphate receptor agonist used in and E2, which may block viral entry into cells. multiple sclerosis. In ChikV infected mice, Fingolimod 2018, CEPI (coalition for Epidemic Preparedness treatment decreased migration of CD4 T-cells into joints Innovation) reported that four vaccines are in phase I trial without affecting viral replication. However, its utility in and two in phase II trial (VLP, MV-Chik). CCA is unknown.1 Phase III field trials are complicated by inability to predict the geographical location and size of next outbreak. Curcumin Turmeric derived compound used as food additive. Newer Mosquito Control Measures

Treatment exhibited antiviral properties through „„ Biotechnology: Introducing insect toxin into fungus 22 inhibition of virus binding to cells in vitro studies. that infects mosquitoes „„ Wolbachia: It is a gram negative bacteria affecting Pimozide and 5-Tetra Decyloxy-2 Fusoic Acid mosquitoes. Large field trial of Wolbachia is underway Found to exhibit synergistic antiviral activity in studies in Yogyakarta, Indonesia, with hope that transmission causing genomic wide loss of function screen.22 of DENV, ChikV can be decreased.

Neutralizing Monoclonal Antibodies-SVIR001 Conclusion Neutralizing IgG MAB to E2 envelope glycoprotein inhibit entry, fusion, and egress of virus. Robust viral clearance ChikV is an arboviral multisystem disease primarily affecting and decreased cytokines and chemokines level have been joints. Chikungunya arthropathy can develop into chronic phase, which may persist for months to years creating distress, observed. disability and debilitating joint pain. Available research Renders protection against multiple alpha virus 22 on treatment options is limited based on which use of including ChikV. DMARDs, corticosteroids, NSAIDs is advised. Newer researches are undergoing to provide evidence-based therapeutic E2 Glycoprotein Mutation options. Vaccine development is under phase II trial. Studies showed the presence of highly conserved Newer therapies have shown benefit in animal models and amino acid on E2 glycoprotein, which promoted ChikV are being studies in human subjects. To prevent the economic persistence in mouse joints. burden that the disease causes, there is an urgent need to formulate universal guidelines and to test newer drugs as well Mutation of this conserved region allowed viral as vaccines. clearance in mice.22

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References 159 cases in Reunion Island from 2006-2012. PLoS Negl Trop Dis. 2015;9(3):e0003603. 1. Joshua B, Kennedy AJ. Clinical features and management of chronic 15. Bouquillard E, Combe B. A report of 21 cases of rheumatoid arthritis chikungunya. 2019. Available from DOI:10.5772/intechopen.86486. following chikungunya fever. A mean follow-up of two years. Joint 2. Himanshu P, Mithun CM, Vinod R, et al. Chikungunya arthritis. Clin Bone Spine. 2009;76(6):654-7. Med (Lond). 2019;19(5):381-5. 16. Amaral JK, Sutaria R, Schoen RT. Treatment of chronic chikungunya . 3 Suhrbier A. Rheumatic manifestations of chikungunya: emerging arthritis with methotrexate: a systematic review. Arthritis Care Res. concepts and interventions. Nat Rev Rheumatol. 2019;15(10):597-611. 2018;70(10):1501-8. 4. Gérardin P, Barau G, Michault A, et al. Multidisciplinary prospective 17. Ravindran V, Alias G. Efficacy of combination DMARD therapy study of mother-to-child chikungunya virus infections on the island vs hydroxychloroquine monotherapy in chronic persistent of La Réunion. PLoS Med. 2008;5(3):e60. chikungunya arthritis: a 24-week randomized controlled open label 5. Mathews AJ, Ravindran V. Infections and arthritis. Best Pract Res Clin study. Clinical Rheumatol. 2017;36(6):1335-40. Rheumatol. 2014;28(6):935-59. 18. Pandya S. Methotrexate and hydroxychloroquine combination . 6 Gabriella S, Isabel B, Laura B, et al. Treatment of chikungunya therapy in chronic chikungunya arthritis: a 16-week study. Ind J arthritis: a systematic review. Rev Assoc Med Bras. 2018;64(1):63-70. Rheumatol 2008;3(3):93-7. . 7 Rodríguez-Morales AJ, Cardona-Ospina JA, Fernanda Urbano- 19. Ribeiro AMBM, Pimentel CM, Guerra ACCG, et al. Physiotherapeutic Garzón S, et al. Prevalence of post-chikungunya infection chronic approach on the late phase of chikungunya: a case report. Rev Bras inflammatory arthritis: a systematic review and meta-analysis. Saúde Matern Infant. 2016;16(Suppl 1):S57-62. Arthritis Care Res. 2016;68(12):1849-58. 20. World Health Organization Regional Office for South-East Asia . 8 Chang AY, Encinales L, Porras A, et al. Frequency of chronic joint Guidelines on clinical management of chikungunya fever. pain following chikungunya virus infection: a Colombian cohort India: WHO, 2008. Available from http://apps.who.int/iris/ study. Arthritis Rheumatol. 2018;70(4):578-84. handle/10665/205178 [Accessed 15 October 2018]. . 9 Blettery M, Brunier L, Polomat K, et al. Brief report: management 21. Marques CDL, Duarte ALBP, Ranzolin A, et al. Recommendations of of chronic post-chikungunya rheumatic disease: the Martinican the Brazilian Society of Rheumatology for diagnosis and treatment experience. Arthritis Rheumatol. 2016;68(11):2817-24. of chikungunya fever. Part 1—Diagnosis and special situations. Rev 10. Cindy L. Chikungunya virus: what every rheumatologist should Bras Reumatol Engl Ed. 2017;57(2):421-37. know. Rheumatol Advisor. 2018;19-25. 22. Zaid A, Gérardin P, Taylor A, et al. Review: chikungunya arthritis: 11. Staikowsky F, Talarmin F, Grivard P, et al. Prospective study of implications of acute and chronic inflammation mechanisms on chikungunya virus acute infection in the island of la Réunion during disease management. Arthritis Rheumatol. 2018;70(4):484-95. the 2005–2006 outbreak. PLoS ONE. 2009;4:e7603. 23. Dagley, Ashley L. Amelioration of chikungunya through inhibition 12. Rendel H. A case of chikungunya virus induced arthralgia of inflammatory response. All graduate thesis and dissertations. responsive to colchicine. Open Forum Infect Dis. 2016;3(2):ofw114. 2016:4996. Available from https://digitalcommons.usu.edu/ 13. Gauri LA, Ashok T, Fatima Q, et Al. Clinical spectrum of chikungunya etd/4996 in Bikaner (North Western India) in 2006 and follow up of patients 24. Yasutaka M. Clinical and radiological features of imported for 5 years. J Assoc Physicians India. 2016;64(3):22-5. chikungunya fever in Japan: a study of six cases at the National 14. Javelle E, Ribera A, Degasne I, et al. Specific management of Center for Global Health and Medicine. J Infect Chemother. post-chikungunya rheumatic disorders: a retrospective study of 2011;17:419-23.

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Atypical Manifestations 164 of Dengue

Ashok Kumar, Shubha Laxmi Margekar, Purnima Margekar, Urvashi Khan

Abstract Globally dengue is the most common arboviral disease being transmitted. Since past five decades disease is rapidly spreading in the world with a 30 fold increase in incidence. The common manifestations of dengue fever includes, fever, retro-orbital headache, generalized body ache, petechial rashes, and bleeding manifestations. Over the period of decades there has been occurrence of other manifestations which are different from typical dengue fever. These manifestations have been called as atypical manifestations and it has been observed that almost all the organ system of body has been affected by dengue fever. Focus of this article is to elaborate the atypical manifestations of dengue fever which also includes the expanded dengue syndrome. Knowledge of these manifestations is necessary to recognize the disease process, limit the complication, and prevent the morbidity and mortality associated.

Introduction The dengue virus infection produces the myriad of clinical symptoms clinical ranging from mild asymptomatic Worldwide dengue is the most common arthropod to febrile illness of unknown origin (can be of viral origin), borne disease, which is being transmitted by the bite of DHF, or dengue fever (DF), or dengue shock syndrome mosquitoes. Since past five decades disease is rapidly 2 spreading in the world, and incidence of dengue infections (DSS) (Table 1). has been rise by approximately 30 times. There is estimated Infection in people who are never been infected 100–400 million people gets infections each year. The first is known as primary or first infection, usually causes confirmed epidemic of dengue hemorrhagic fever (DHF) classical dengue fever. Subsequent or secondary infection was recorded in the Philippines in 1953–1954 and in India by different dengue virus serotype causes more severe it occurred in Calcutta in 1963. Although it is a preventable illness like dengue DHF/DSS. Major pathophysiologic disease but it also has high mortality and morbidity. Due changes occurring in DHF/DSS are: to lack of awareness among the health-care personnels, „„ Plasma leakage atypical presentation is often missed and goes unreported. „„ Rising hematocrit Dengue virus belongs to the virus of genus flaviviruses of „„ Thrombocytopenia, and Flaviviridae family. There are various serotype of dengue „„ Bleeding manifestations. virus are there namely DEN 1-4. The vector responsible It’s an acute febrile illness with rash, arthralgia, for the spread of dengue virus is mosquito Aedes aegypti leukopenia, headache, retro-orbital pain, hemorrhagic (A. aegypti).1 Infected Aedes mosquitoes, especially A. manifestations.2 As per WHO clinical diagnosis of DHF is aegypti, transmit various serotypes to humans through made by the following criteria:1 their bites. „„ Continuous spikes of high grade fever for 2–7 days

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TABLE 1 Manifestation of dengue virus infection

Asymptomatic Symptomatic Undifferentiated Dengue fever Dengue hemorrhagic fever Expanded dengue syndrome/ fever (Viral (Classical) (Classical) Isolated organopathy syndrome) (Unusual presentation) Without With unusual Without With shock hemorrhage hemorrhage shock dengue shock syndrome (DSS)

Flowchart 1: Expanded dengue

„„ Positive tourniquet test or presence of bleeding diagnostic dilemma some atypical manifestation are tendency often missed and being underreported. Henceforth, „„ Platelet count <100,000/µL a new term Expanded Syndrome has been coined by „„ Evidence of hemo-concentration, i.e., 20% rise in WHO, in the revised classification in 2012 as shown in hematocrit as per average for age, sex, and population, Flowchart 1.2,3 Atypical manifestations are correlated presence of ascites and pleural effusion with neurological, renal, hepatic, cardiovascular, and One of the life threatening complications is DSS, which other organs involvement (Table 2). It has been reported is characterized by DHF (meeting all four criteria) along increasingly in DHF and also in dengue patients with no with circulatory failure. Circulatory failure is manifested by evidence of leakage of plasma. Most DHF patients who rapid and weak pulse, cold clammy skin and restlessness have unusual manifestations are the result of prolonged and narrow pulse pressure (<20 mm HG) or hypotension shock with organ failure or patients with comorbidities or 2 for age. coinfections.

Atypical Manifestations Neurological Manifestations The classic presentation of dengue has been expanded The association between DHF and neurological with involvement of various organ systems. Due to disturbances were first described in 1976.4,5 Different

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TABLE 2 Atypical manifestations of dengue

Neurological Gastrointestinal/Hepatic Renal Cardiac Respiratory zz Febrile seizures zz Hepatic failure (Fulminant) zz Acute renal failure zz Myocarditis zz Acute respiratory zz Encephalitis zz Acalculous cholecystitis zz HUS zz Pericarditis distress syndrome zz Encephalopathy zz Acute pancreatitis zz Conduction abnormalties zz Pulmonary zz Transverse myelitis zz Acute parotitis hemorrhage Lymphoreticular/bone marrow Musculoskeletal Eye Others zz HLH Rhabdomyolysis Optic neuritis Psychosis zz ITP zz Spontaneous splenic rupture zz Infarction of lymph node

manifestations including neurological signs may occur whose NCV, i.e., nerve conduction velocity and EMG, i.e., due to neurotropicity, which is due to direct invasion electromyography were completely normal.11,12 Further of tissue, release of cytokines damaging the blood unusual manifestation observed in the same study was brain barrier, brain edema, capillary leakage can be that of spinal cord involvement including ATM, i.e., acute leading to bleeding manifestations involving intracranial transverse myelitis, which was managed with steroid, hemorrhage, and due to extended period of shock there i.e., methylprednisolone and IVIG. Muscle involvement could be hypoperfusion of brain, acute renal injury, liver also seen in the form of Myalgia cruris, which may be dysfunction, and electrolyte imbalances like decrease due to direct muscle invasion by virus causing damage to in the sodium levels, i.e., hyponatremia and decrease muscle or may be due to released cytokines.13 Another rare in the blood glucose levels, i.e., hypoglycemia.6,7 In manifestation is dysarthria clumsy hand syndrome. the study by Pancharoen and Thisyakorn (2001) they explained that altered sensorium is the most usual Gastrointestinal Manifestations neurological finding subsequently seizures were noted Gastrointestinal presentations of virus are such as febrile among 75% of patients with DSS.5 Various other patients diarrhea, fulminant liver failure, inflammation of pancreas, had manifestations of PN (polyneuropathy), Encephalitis, i.e., acute pancreatitis, cholecystitis mostly acalculous, memory loss, and myelitis.8 Meningitis was found in severe inflammation of parotid gland, i.e., acute parotitis. (1.2%).9 In a study conducted by Pothapregada et al. Severe pain abdomen is one uncommon manifestation (2016),10 neurological manifestations were observed seen in dengue. With such presentation, acute peritonitis, in 28 children (11%). In the same study total six deaths acute pancreatitis, or acalculous cholecystitis should be (2.4%) were there and out of them four presented with ruled out. Diverse involvement of virus in liver scales impaired consciousness (66. 6%) during admission with from advancing from meagre symptoms of increasing their GCS < 8. Multiorgan failure, refractory shock, and liver enzymes to a full-blown liver failure or fulminant encephalopathy were accounted for the poor outcomes. hepatic failure. Elevation of liver enzymes (AST/ALT) is Mohanty et al.11 described in his study that fever and seen commonly in dengue infection. Elevation of liver altered sensorium were related to typical presentation enzymes like AST/ALT is commonly seen in patient with of the virus, CSF analysis suggestive of viral encephalitis, dengue fever and 9th day of the illness is the most crucial five deaths due to multiorgan dysfunction, cerebral day where the liver enzymes tend to increase from the infarct in neuroimaging seen in one patient. Potassium day of onset of symptoms and it gradually progresses redistribution in the cells also played an important part toward normal within 3 weeks.6,7 Another illustration in neurological manifestation caused by dengue, which of acalculous cholecystitis introduces abdominal pain leads to a rare entity described as Hypokalemic periodic specifically localized to the upper quadrant in the right paralysis. In the study by Mohanty et al.11 they found that side, uninterrupted fever and positive elicitation of patients responded well with potassium infusion who Murphy’s sign. Exact mechanisms are not known, it might had features suggestive of hypokalemic paralysis and be due to invasion by the virus in the gall bladder wall

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giving rise to edema of gall bladder and microangiopathic Coinfections 10 injury, which itself is self-limiting. Cholecystectomy not It modifies the presentation of dengue clinically and recommended due to thrombocytopenia as postoperative results in delayed diagnosis and treatment of dengue bleeding. Except in case of peritonitis, gangrene and shock. perforation where surgical intervention is required.6 Malaria Cardiovascular Manifestations Malaria is the most common infection, which can be Cardiac demonstrations of the virus are uncommon found with dengue infection. Because of the similar though cardiac rhythm abnormalities like AV blocks, Atrial seasonal variations in the incidence of both infections fibrillations, dysfunction in sinus node and ectopic beats and similar clinical presentation and even similarity in in ventricles have been noticed during DHF incidents. laboratory parameters sometimes the diagnosis of dengue The physiopathology of cardiac leads to inflammation can be very challenging and coinfection with malaria causing cytokine storm of both structural and functional can be missed which can lead to fatal outcome. Among 11 integrity by the virus. If clinically and ECG findings are the four species of plasmodium, as per Indian studies suggestive of myocarditis, CPK-MB is considered the most P. faliciparum is commonly associated. Its presenting precious investigation to correlate, whereas tachycardia features are headache, myalgias, backache, hypotension, and volume depletion are suggestive of poor outcome. hepatosplenomegaly. Suspicion and treatment of complicated malaria is necessary for prevention of fatal Renal Manifestations outcome. Dengue virus also affects renal system leading to acute kidney injury and it exhibits as acute tubular necrosis Zika Virus Disease (ATN), which is a rare manifestation and mostly attributed It is confirmed after exclusion of dengue infection with due to shock. ARF in these individual is of pre-renal origin. serological tests. As compared to dengue virus infection, There could be various methods but the approved ones symptoms in Zika virus infection are mild fever, mild body are that of invasion by the virus directly into the renal ache, ill-defined rashes but no hemorrhage. system, i.e., kidneys or immune mediated. Management with appropriate fluid in hyperkalemia unresponsive Chikungunya to conventional treatment, decrease urine output, and Aedes aegypti is common vector for both Chikungunya uremia hemodialysis is to be used for management. as well as dengue. Arthralgia common in both, but in dengue it is self-limiting and latter can progress to Respiratory Manifestations disabling arthritis, which may persist for months. Also Unexceptional manifestation in the respiratory system thrombocytopenia can be found in both infections. caused by the dengue virus is that of ALI, i.e., acute injury to lung and acute distress to the respiratory system, i.e., ARDS. Conclusion These manifestations in turn lead to edema of alveolus and The most effective way to prevent dengue virus transmission also there is increased permeability in the alveolar capillary is to combat the disease-carrying mosquitoes. Effective membrane. Better outcomes can be achieved by early vector control strategies appear to be promising for dengue identification and treatment. If pulmonary hemorrhage prevention and control. Risks associated with the disease can occurs, it becomes the fatal complication. be assessed with the timely diagnosis and initiation of medical care. Recognizing expanded dengue syndrome in early stage Musculoskeletal Manifestations is crucial for optimizing treatment strategies. A high index of Dengue myositis: It is manifested as break bone fever, suspicion of features of expanded dengue syndrome (EDS) is severe muscle, bone, and joint pain. There is elevated very important for targeting treatment option. Alteration in SGOT, SGPT, and creatine phosphokinase. Direct invasion sensorium is most devastating atypical manifestation in case of severe dengue infection, which, if not recognized in time, may of muscles by viruses has not been proven and may appear lead to fatal outcome. to be myotoxic cytokines, particularly TNF.

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References . 7 Verma R, Sharma P, Garg RK, et al. Neurological complications of dengue fever: experience from a tertiary centre of north India. Ann 1. WHO Dengue Hemorrhagic Fever: Diagnosis, Treatment, Prevention Indian Acad Neurol. 2011;14(4):272-8. and Control, 2nd edition. Geneva: World Health Organization. Who. . 8 Siddiqi Z, Fatima J, Karoli R, et al. A study of typical and atypical int. 2019;84. Available from https://www.who.int/csr/resources/ clinical manifestations in dengue patients. Era’s J Med Res. publications/dengue/ Denguepublication/en/. 2019;6(2):57-62. 2. Comprehensive Guidelines for Prevention and Control of Dengue . 9 Mohan K, Malaiyan J, Nasimuddin S, et al. Clinical profile and and Dengue Hemorrhagic Fever [Internet]. South-East Asia atypical manifestation of dengue fever cases between 2011 and Regional Office. 2019. Available from http://www.searo.who.int/ 2018 in Chennai, India. J Family Med Prim Care. 2020;9(2):1119-23. entity/vector_borne_tropical_diseases /document s/SEAROTPS60/ 10. Pothapregada S, Kamalakannan B, Thulasingam M, et al. Clinical en/ profile of atypical manifestations of dengue fever. Indian J Pediatr. 3. Kadam DB, Salvi S, Chandwale A, et al. Expanded syndrome, review 2016;83(6):493-9. article. J Assoc Physicians India. 2016;64(7):59-63. 11. Mohanty B, Sunder A, Pathak S, et al. Clinico-laboratory profile 4. Solomon T, Dung NM, Vaughn DW, et al. Neurological manifestations of expanded dengue syndrome—our experience in a teaching of dengue infection. Lancet. 2000;355(9209):1053-9. hospital. J Family Med Prim Care. 2019;8(3):1022-7. 5. Pancharoen C, Thisyakorn U. Neurological manifestations in dengue 12. Jha S, Ansari MK. Dengue infection causing acute hypokalemic patients. Southeast Asian J Trop Med Public Health. 2001;32(2): quadriparesis. Neurol India. 2010;58(4):592-4. 341-5. 13. Ahmad R, Latiff AKA, Razak SA, et al. Myalgia cruris epidemica: an 6. Gulati S, Maheshwari A. Atypical manifestations of dengue. Tropical unusual presentation of dengue fever. Southeast Asian J Trop Med Med Int Health. 2007;12(9):1087-95. Public Health. 2007;38(6):1084-7.

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Cholera and Plague—Is the 165 Threat Over?

Shyam Chand Chaudhary, Chitranshu Pancholi, Kamal Kumar Sawlani, Deepali Mohanty

Abstract Cholera and plague both are communicable diseases which are preventable by targeted multisectoral approach including improvement of sanitation, education regarding good hygiene practices, improvement of housing, and quality of life. As per the WHO, cholera cases have decreased globally and there is a significant downward trend in incidence. WHO has planned a global road map to reduce the cholera-related deaths by 90% till 2030. Plague can also be controlled by breaking the chain of transmission, proper application of insecticides, early identification, notification, isolation, and treatment by appropriate antibiotics.

Introduction responsible for previous six pandemic and El Tor was responsible for seventh one starting in 1961. In 1992, O139 Cholera is often predictable and preventable public was identified as a cause of extensive cholera epidemic in health problem, which poses a global threat. It is an various part of South Asia including India and Bangladesh. indicator of lack of access to clean water and sanitation Humans become infected incidentally but, once infected, facilities. Good hygiene practices can eliminate cholera.1 can acts as a vehicle for spread. There is no animal Pandemics of plague occurred from time to time in the reservoir. Ingestion of contaminated water and food by past, but nowadays it can be treated and prevented easily human feces are the common means of acquisition of by use of effective antibiotics and standard measures for 2 V. cholera. Risk factor include poor hygiene, poor water prevention. supply, lack of sanitation (peri-urban slums, refugee camps), etc.3 Cholera Cholera is caused by toxin producing strain of Vibrio Epidemiology cholerae, which is curved shaped Gram-negative, highly WHO standard case definition: Suspected cholera case— motile with single polar flagellum bacterium. It causes when a patient aged ≥5 years develops severe dehydration acute diarrhea and is known as “Father of public health.” or dies because of acute diarrhea in an area where the There are more than 200 serogroup of V. cholera. Of disease is not known to be present or when patient these, only two toxigenic serogroups O1 and O139 cause aged ≥5 develops acute watery diarrhea with or without outbreaks. El Tor and classical are the two biotypes of vomiting in cholera epidemic area. Confirmed cholera serogroup O1. In comparison to classical strains, El Tor case—any suspected case in which Vibrio cholerae O1 biotype causes more of asymptomatic cases and exists or O139 is confirmed by culture or polymerase chain in environment for longer time. Classical strain was reaction (PCR) test. Cholera endemic area—an area

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where cholera confirmed cases have been detected in Symptoms last 3 years due to local transmission. Cholera outbreak is Incubation period is 2 hours to 5 days. Most of the cases defined by the occurrence of at least one confirmed case of (around 75%) are asymptomatic and shed bacteria for cholera and evidence of local transmission or unexpected 1–2 weeks in their feces. Those who are symptomatic, increase (in magnitude or timing) of suspected cases over the majority have mild to moderate symptoms and few two consecutive weeks, of which some are laboratory patients’ presents with sudden onset explosive, painless, confirmed cases in an area with sustained (year-round) non-bilious “Rice water stools”. It is not associated with transmission.4 blood and typically fishy, inoffensive odor. Stool of In 19th century, cholera spread across the world from Ganges delta in India and killed millions of people in seven cholera patient contains higher concentration of sodium, subsequent pandemics. More than 40% of cholera cases potassium, and bicarbonate. It is usually associated reported annually to the WHO are from Africa, more than with vomiting and severe dehydration even can be life 3 35% from Asia, and more than 20% from the Americas.3 threatening (cholera gravis). It can lead to hypotensive Researchers have estimated that every year, there are 1.3– shock, renal failure and that can be fatal in 50–70% 4.0 million cases of cholera, and 21,000–143,000 deaths cases, if dehydration is not addressed properly. Other occurs worldwide due to the infection.5 In year 2017, 34 clinical symptoms are parallel to volume contraction countries reported 5,644 deaths and 122,7391 cases which (Table 1). Severity of illness depend on various factors came down to 2,990 deaths and 499,447 cases in the year including number of V. cholera bacteria ingested, neither 2018. As per WHO, number of cholera cases decreased exposed previously nor vaccinated, lack of passive globally (60% in 2018) and significant downward trend is immunity in new born (no breast feeding), pregnancy, continued; however, outbreaks are still ongoing in various immunocompromised conditions, malnourishment, countries. reduced gastric acid production, and blood group O.

TABLE 1 Clinical features and treatment of cholera according to severity

Degree of Loss of Clinical findings Treatment dehydration TBW Fluid Adjunctive antibiotics Zinc Supplementation (Treatment of choice) (In moderate to severe cases) Mild <5% Thirst zz ORS required in first 4 - Recommended in hours is equal to weight children for 10 days Moderate 5–10% Thirst, weakness, in kg multiplied by 75 in Drug of Choice zz <6 month–10 mg/day postural hypotension, mL. zz Azithromycin 1 gm single zz 6 months to 5 tachycardia, zz As for as daily dose in adult (20 mg/kg in years–20 mg/day decreased skin turgor, requirement is concern, it children) OR dry mouth/tongue, should be given as much zz Erythromycin-250 QID for no tear as patient can have desire 3 days to drink until signs of zz Second choice dehydration subsides zz Doxycycline in non- pregnant adult—300 mg Severe >10% Unconsciousness, IV Fluids single dose OR zz Tetracycline (non-pregnant lethargy or zz Ringer lactate (Preferred) floppiness, inability or Normal saline adult)—500 mg QID for 3 days to drink, sunken eyes, zz 100 mL/kg in first 3 zz weak or absent pulse, hours (in first 6 hours for Third choice zz decreased urine children <12 months old) Ciprofloxacin 500 BD in output, hypotension to a total of 200 mL/kg in adult and 15 mg/kg BD in or shock 24 hours children for 3 days zz Further requirement of fluids depends on patient condition

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Cholera sicca, another form of cholera, presents level teaspoon) dissolved in 1 liter drinking water may be with fluid accumulation in intestinal lumen, circulatory safely used until the proper solution is available. Severe collapse and even death in absence of diarrhea. Fever is cases need urgent hospitalization and intravenous fluid usually absent and muscle cramps are common due to resuscitation (typically 10–20 mL/kg/hour). Ringer lactate electrolyte imbalance.3 is fluid of choice as it also corrects the acidosis along with electrolytes.3 While transfusing the fluid regular monitoring Diagnosis for signs of dehydration including urine output, vitals, and Diagnosis requires high index of clinical suspicion with chest examination are warranted. Though the rehydration severe acute watery diarrhea. Detection of V. cholerae therapy is the main stay of treatment but it neither reduces from stool by dark field microscopy or isolation from the duration of the disease nor excretion of bacteria in stool culture on selective TSBS agar (thiosulfate citrate feces. Antibiotic are added in moderate to severe cases to bile sucrose) or TTGA (taurocholate tellurite gelatin agar) decrease duration of illness, reduce volume needed for remains the standard test. PCR method is also becoming rehydration and hastens the clearance of the organism available for diagnosis. Several rapid diagnostic tests from the stool (Table 1). Oral supplementation of Zinc in (RDTs) such as immune chromatographic lateral flow children of 6 months to 5 years, reduces the severity as well 3 devices (dipsticks), which detect the presence of the O1 or as prevent the recurrence of diarrhea. O139 antigen in rice water stool samples (sensitivity—95% and specificity—65–85%). RTDs can be performed Prevention by semi-skilled workers and it provides point of care Cholera can be prevented by access to potable drinking diagnostic facility.3 water, adequate sanitation, educating people regarding good hygiene practices (frequent hand washing with soap, Treatment proper disposal of excreta and avoiding consumption of In severe cases, rapid rehydration (oral rehydration food in unhygienic environment). Cholera vaccinations solution or intravenous fluid) is the primary treatment is a complimentary prevention and control measure 3-8 for cholera. About 90–95% of all cholera cases can be (Table 3). treated by oral fluid alone. Mild to moderate dehydration In 2018, WHO passed a global road map to reduce cases are treated by reduced osmolarity oral rehydration the cases of cholera by 90% till 2030 by focusing on three 9 solution (WHO/UNICEF ORS). Composition of reduced following strategies: osmolarity ORS is given in Table 2. Oral rehydration „„ Early detection of cholera cases and contains outbreaks solution is prepared by dissolving one standard sachet rapidly in a 1 liter of clean water. In absence of ORS, mixture „„ Prevention of cholera recurrence by targeting consisting of table salt (one level teaspoon) and sugar (6 multisectoral approach „„ An effective mechanism of coordination for technical support, resource mobilization, and partnership at different levels TABLE 2 Composition of reduced osmolarity ORS* Constituent Concentration (mmol/L) Plague Sodium 75 Plague is caused by Yersinia pestis, Gram-negative Potassium 20 coccobacilli, bipolar in appearance (closed safety pin), Chloride 65 non-capsulated, facultative anaerobic, non-motile, Citrate 10 organism of family Enterobacteriaceae. Human acquires Glucose, anhydrous 75 infection via bites of infected rodents, fleas, or infected Total osmolarity 245 domestic cats, direct contact with infected human, animal *Per sachet (to be added to 1 L of drinking water) contains: NaCl—2.6 tissue or body fluids, inhalation of infected respiratory gm; tri-sodium citrate dehydrate—2.9 gm; KCl—1.5 gm; Glucose droplets from a patient with pneumonic plague or (anhydrous)—13.5 gm respiratory secretions from infected animals. Consumption

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TABLE 3 Oral cholera vaccine3-8

Oral killed cholera vaccines Oral live attenuated Killed whole-cell monovalent vaccine with recombinant Three bivalent whole-cell only CVD 103-HgR (Vaxchora) cholera toxin B subunit (WC-rBS) vaccines (Biv WC), Based on sero- groups O1 and O139 of V. cholerae zz Dukoral (First licensed in Sweden) Schanchol (licensed in India in 2009), Approved by USFDA in 2016 for mORVAX (licensed in Viet Nam in 1997 travelers to cholera endemic area for use in endemic region in 2009 for domestic use), Euvichol (licensed in the Republic of Korea), Shanchol and Euvichol produced for International markets, available in single dose vials zz Vaccine contains a mixture of the recombinant B WC vaccines do not contain the Engineered attenuated V. cholerae O1 subunit (rBS) of cholera toxin (1 mg per dose) plus bacterial toxin B subunit and therefore classical Inaba strain CVD 103-HgR formalin/heat killed whole cell of V. cholera O1 do not protect against ETEC (classical and El Tor, Inaba and Ogawa) zz Because of toxin, vaccine provides some protection to Enterotoxigenic E. coli (ETEC) zz To protect the toxin from gastric acid, it must be given with bicarbonate buffer zz Vaccine is available in 3 mL, single dose vials together Euvichol and Shanchol: 1.5 mL zz There are two sachets, one contains with the bicarbonates buffer (effervescent granules in glass vial with rubber stopper and lyophilized vaccine and another as sachets) aluminum lid buffer powder zz Vaccine and buffer should be dissolved in 150 mL zz Reconstitution is done by mixing of water in children >6 years and adult, in 75 mL for the both sachet in 100 mL water children <5 years and it should be consumed within zz Intake of food and water should be avoided 1 hour 15 minutes of reconstitution in a before and after the vaccination single dose Primary immunization Two doses are given at an interval of Approved for the use in 18–64 years zz Not licensed for use in <2 years of age 14 days in persons with age ≥1 year of age zz Children 2–5 years of age, 3 oral doses given 7 days—6 weeks apart zz Two doses are recommended in adults and children >6 years. Interval between the dose should be at least 7 days but not >6 weeks zz If second dose is not administered within 6 weeks after the first dose, whole schedule should be repeated Booster dose No recommendation regarding No recommendation regarding zz Children 2–5 years—booster dose every 6 month booster dose exists timing and use of booster is currently of primary immunization. If booster dose is not available, probably because it provides administered in time, whole schedule should be long-term immunity after a single oral repeated dose zz Children age >6 years and adults—booster dose every 2 years. If booster dose is not administered in time, whole schedule should be repeated Protection Between 80–90% efficacious against zz Provides 60–85% protection for the first few months severe cholera at 10 and 90 days after zz 60% protection over 5 years among recipient of all age vaccination respectively zz 40% protection among children ≤5 years of age zz If cold chain (2–8°C) is maintained. Self-life is 3 years. It Self-life is 2 years at maintenance of Cold chain temperature stable only for 1 month at 37°C cold chain (2–8°C) and remains stable (−25 to −15°C) for 14 days at 42°C zz Can be safely given in among populations with high rate of HIV infection and in pregnancy Safety in pregnancy is not established

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of contaminated food and laboratory exposure are also the the direct inhalation of bacteria into the lungs. It manifests source of infection. During bioterrorist attack, primary earlier, having incubation period of few hours to few days. pneumonic plague caused by aerosolized Y. pestis bacteria It starts with non-specific symptoms, then progresses in non-endemic areas is a public health problem.10 to dyspnea, chest pain, cough, sputum production, hemoptysis, tachypnea, and signs of hypoxemia and Epidemiology toxemia. Secondary pneumonic plague—It is more „„ Three major plague pandemics have been recorded common form and is caused by hematogenous spread in human history: the “Plague of Justinian” in the 6th of bacteria to the lungs from a bubo or other source. Ten century, again in the 14th century (known as the “Black to fifteen percent of bubonic plague patients develop Death,” which killed up to one-third of the European secondary pneumonic plague, if treatment of bubonic population or an estimated 17–28 million people, plague is delayed. Diffuse alveolar infiltrates of chest X-ray, and at the end of 19th century following the spread of and interstitial pneumonitis on computed tomography infection from China. are typical of pneumonic plague. Untreated pneumonic „„ Plague is prevalent in all part of the world except, plague is almost always fatal, and mortality is very high. Oceania. Septicemic Plague: It occurs in 10–20% of cases in „„ Peru, Madagascar, and the Democratic Republic of advance stages of the disease. Patient is febrile having Congo are the most endemic countries. gastrointestinal symptoms and present as Gram- „„ Plague does occur in Asia, but is restricted to breeders negative septicemia (hypotension, shock, disseminated and hunters since the reservoir consists mainly of intravascular coagulation, and multiorgan failure). gerbils in the steppe and marmots in the mountains. Risk factors for septicemic plague include, age more „„ During epidemic season, cases of bubonic plague are than 40 years, diabetes mellitus and hemochromatosis. reported every year in Madagascar. Their diagnosis is difficult because it occur without any preceding bubo. Symptoms Symptoms of plague usually develop after an incubation Other Types period of 1–7 days. Initial symptoms are nonspecific Meningitis: It can occur as primary manifestation as including high grade fever, headache, sore throat, body result of occult bacteremia or associated with bubonic, ache and generalized weakness. Specific symptoms pneumonic, septicemia plague. It resembles to bacterial 11 depend upon types of plague. meningitis by symptoms and CSF examination (low Bubonic Plague: Most common form (80–95% cases) glucose, increased protein with neutrophilic pleocytosis). of plague. Apart from nonspecific symptoms, there is Pharyngitis and Tonsillitis: Manifest with nonspecific rapidly progressive, painful lymphadenitis (known as symptoms along with anterior cervical lymphadenitis. “bubo”). The common sites for lymphadenitis are regional Patient with no symptoms can act as carrier for bubonic lymph nodes, and near the site of flea bite. Suppuration plague cases. In approximately 14% cases, involvement over buboes can occur and it is differentiated from of GIT and urinary tract is also seen. Some patients may other conditions by absence of cellulitis and ascending present with multiple organ failure and die without lymphangitis. Case fatality rate in untreated bubonic diagnosis, if symptoms are non-specific without bubo and plague is higher (50–90%) in comparison to treated cases there is no outbreak of plague in that geographical area.10,11 (10–20%), mostly because of disseminated infection. In advanced stage it causes secondary pneumonic plague Laboratory Investigations and meningitis due to spread to the lungs and brain, In plague endemic areas, neutrophilic leukocytosis respectively. Bubonic plague patients can presents with (10,000–100,000/µL) with left shift, normal or low-normal abdominal discomfort. platelets and symptoms (fever, unexplained regional Pneumonic Plague: Depending on the type of exposure it lymphadenitis, and hypotension) with known contact with is of two types; Primary pneumonic plague—caused by dead rodents is diagnostic clue. Blood culture is positive

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in 27–96% cases. Y. pestis can be cultured from pus from is excluded or patient is treated for 48 hours with bubo in bubonic plague, from sputum or broncoalveolar effective drugs, because they can spread the disease by lavage sample in pneumonic plague, from blood in aerosol generation. septicemic plague and from CSF in meningitis. Peripheral „„ Maximum infectivity is in final stage of disease when blood smears, microscopic aspirate of bubo may show rod patients are coughing sputum with plenty of blood shaped organism with Wright-Giemsa stain and typical or pus. Though simple cotton mask or surgical masks bipolar staining as “closed safety pin” on Wayson’s stain. usually provides barrier protection against droplets but Serologic testing of single titer of >1:16 of F-1 antigen of WHO recommends personal protective equipment’s Y. pestis by passive hemagglutination test is diagnostic. for potential aerosol generating procedures and Rapid diagnostic test can detect F-1 antigen of Y. pestis (0.5 should include an N-95 face mask, a gown, gloves, and ng/mL) within 15 minutes in serum and sputum in field a face shield or goggle.8 8,9 10 testing. WHO case definition is given in Table 4. „„ Appropriate antibiotic treatment of cases: It should be initiated within 24 hours, ideally after specimen for Plague Outbreaks Managements12 culture are obtained. It is continued for 10–14 days „„ Find out the suspected case: During epidemic situation or a course can be continued until 2 days after fever 10,11,13 diagnosis of suspected case is based on clinical ground subsided (Table 5). (acute febrile illness with painful lymphadenopathy) „„ Surveillance: Identification and monitoring of and in other situation rat falls (dead rats) provide a individuals having history of close contact. useful warning of a possible outbreak. Suspected case „„ Disinfection: Disinfection by hand washing with soap should be confirmed bacteriologically. and water, use of alcohol based hand rubs or house „„ Notification of each and every human or rodent plague made disinfectant (10% diluted bleach). case. „„ Ensure safe burial practices: Proper disposal of dead „„ Isolation: Isolation of suspected pneumonic plague body of a suspected pneumonic plague patient should patients is recommended until either the pneumonia be ensured.

TABLE 4 WHO case definition of plague10

Suspected case Compatible clinical presentation and consistent epidemiologic features, such as exposure to infected animals or humans and/or evidence of flea bites and/or residence in or travel to a known endemic focus within the previous 10 days Presumptive case Meeting the definition of a suspected case plus Putative new or reemerging focus: ≥2 of the following tests positive zz Microscopy: Gram-negative coccobacilli in material from bubo, blood, or sputum; bipolar appearance of Wayson or Wright-Giemsa staining zz F1 antigen detected in bubo aspirate, blood, or sputum zz A single anti-F1 serology without evidence of previous Yersinia pestis infection or immunization zz PCR detection of Y. pestis in bubo aspirate, blood, or sputum Known endemic focus: ≥1 of the following tests positive zz Microscopic evidence of Gram-negative or bipolar (Wayson, Wright-Giemsa) coccobacilli from bubo, blood, or sputum zz A single anti-F1 serology without evidence of previous plague infection or immunization zz F1 antigen detected in bubo aspirate, blood, or sputum Confirmed case Meeting the definition of a suspected case plus zz Identification of an isolate from a clinical sample as Y. pestis (colonial morphology and two of the following four tests positive: phage lysis of cultures at 20–25°C and 37°C; F1 antigen detection; PCR; Y. pestis biochemical profile) or zz A fourfold rise in anti-F1 titer in paired serum samples or zz In endemic areas when no other confirmatory test can be performed, a positive rapid diagnostic test with immunochromatography to detect F1 antigen

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TABLE 5 Treatment of plague cases

Drugs Dose Streptomycin 30 mg/kg/day (up to total dose 2 gm) in two divided doses intramuscular (Preferred-FDA approved) Gentamicin 2 mg/kg loading dose followed by 1.7 mg/kg every 8 hourly intravenously (in children 2.5 mg/kg IV every 8 hours) Doxycycline 200 mg loading dose on first day followed by 100 mg every 12 hourly orally or intravenously in adult and child ≥45 kg, child <45 kg—2.2 mg/kg (maximum, 100 mg/dose) IV every 12 hours Tetracycline Oral 2 gm loading dose followed by 2 gm/day in four divided doses (not indicated in children <7 years of age) Levofloxacin Adult and child ≥50 kg—500 mg OD oral or intravenously, child <50 kg and ≥6 months of age—16 mg/kg (maximum 250 mg/dose) oral or intravenously every 12 hours Ciprofloxacin 400 mg IV every 12 hours or 500 mg orally every 12 hours in adult In children—15 mg/kg IV every 12 hours or 20 mg/kg orally every 12 hours Chloramphenicol In adult and child >2 years—100 mg/kg (maximum, 4 gm) in four divided doses (oral or intravenous), very useful in plague meningitis because of its ability to penetrate the blood brain barrier

„„ Protect health workers: Training of health workers about (dust containing DDT 2%, BHC 2%, Malathion 5%, and infection prevention and control measures. Workers Carbaryls 2%) are used. Rat borrows should be insufflated having history of close contact with pneumonic with the insecticidal dust. This must precede or coincide plague patients should take 7 days chemoprophylaxis. with anti-rodent measures. Disinfection, distancing, and PPE should be used Control of Rodents: Control of rodents is an important appropriately. plague preventive measure. It improves with improvement of general sanitation, improvement of housing and quality Prevention of life.14 Prophylaxis: Post-exposure prophylaxis is recommended to individuals with unprotected close contact (face to face Conclusion or 1–2 meter) with suspected or confirmed pneumonic plague and family members of a bubonic plague patient. Though the number of cholera cases has been decreased Oral doxycycline 100 mg twice daily for 7 days or oral in India, but the social, epidemiological, and ecological levofloxacin 500 mg once daily for 10 days are used for conditions in remote areas continue to favor the occurrence. this purpose. In pregnancy double strength tablet of co- World Health Organization has planned to reduce the cholera-related deaths by 90% till 2030. They focused on trimoxazole twice daily and in children trimethoprim 4 three important strategies; early detection of cholera cases mg/kg twice daily has been used safely.11 and rapid response to contain outbreaks, prevention of Vaccination: A whole cell killed vaccine given at least a recurrence by targeted multi-sectoral approach, and an week before anticipated outbreak as its immunity starts effective mechanism of coordination for technical support, after 5–7 days of first dose vaccine. Two subcutaneous resource mobilization, and partnership at different levels. doses of 0.5 mL and 1 mL, at an interval of 7–14 days Like cholera cases, a number of plague cases are also reduced due to good availability of effective drugs, improvement of are given. Booster dose is recommended 6-monthly for sanitation, improvement of housing and quality of life. Primary persons at continuing risk of infection as its immunity pneumonic plague caused by aerosolized Y. pestis is having persists for 6 months. Vaccination is also recommended high fatality rate. As Y. pestis has the capacity to infection for travelers to endemic areas and those having increased through aerosol, it fits into the category of a potential agent risk of disease. of bioterrorism. Its outbreak should be identified as soon as possible and appropriate steps should be followed for its Control of Fleas: To break the chain of transmission management. (rodent->flea->man) proper application of insecticides

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References 8. Levine MM, Chen WH, Kaper JB, et al. PaxVax CVD 103-HgR single- dose live oral cholera vaccine. Expert Rev Vaccin. 2017;16(3):197-213. . 1 World Health Organization. Available from https://www.who.int/ . 9 WHO fact sheet on cholera, 17 January, 2019. Available from health-topics/cholera https://www.who.int/news-room/fact-sheets/detail/cholera . 2 World Health Organization. Available from https://www.who.int/ 10. Prentice MB. Plague and other Yersinia infections. In: Jameson JL, health-topics/plague Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J (Eds). Harrison’s . 3 Waldor MK, Ryan ET. Cholera and other vibrioses. In: Jameson JL, Principles of Internal Medicine, 20th edition. New York: McGraw Hill Fauci AS, Kasper DL, et al. (Eds). Harrison’s Principles of Internal Professional; 2018. pp. 1200-8. Medicine, 20th edition. New York: McGraw Hill Professional; 2018. 11. Tauxe RV. Clinical manifestations and diagnosis of Yersinia infections. (www.uptodate.com-Last literature review: May 2020). pp. 1186-92. 12. World Health Organization. Fact sheet-Plague. Available from . 4 World Health Organization. Weekly Epidemiological Record. URL:http://www.who.int/mediacentre/factsheets/fs267/en 2017;92(34):477-500. [Accessed on October 10, 2017]. 5. Park K. Cholera. Park’s Textbook of Social and Preventive Medicine, 13. Narayanan N, Lacy CR, Cruz JE, et al. Disaster preparedness: 25th edition. India: Bhanot Publishers; 2019. pp. 251-7. biological threats and treatment options. Pharmacotherapy. 6. Weekly Epidemiological Record. WHO. 2018;93(38):489-500. 2018;38(2):217-34. . 7 Wierzba TF. Oral cholera vaccines and their impact on the global 14. Park K. Plague. Park’s Textbook of Cocial and Preventive Medicine, burden of disease. Hum Vaccin Immunother. 2019;15(6):1294-301. 25th edition. India: Bhanot Publishers; 2019. pp. 319-24.

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Cryptococcal Disease: 166 A Review

VK Sashindran, Rajneesh Thakur

Abstract Cryptococcosis is an opportunistic mycosis which was uncommonly identified before the HIV/AIDS pandemic. It is responsible for high mortality among people living with HIV/AIDS (PLHA) and also among other non-HIV immunocompromised people. Cryptococcus is one of the four fungal species accounting for almost 90% of fungal infection- related deaths in the world, the other three being Candida, Aspergillus, and Pneumocystis. C. neoformans is found in high concentrations in bird guano and C. gattii in decaying vegetation especially that of the Red River gum trees (Eucalyptus camaldulensis). The preferred sites of infection by C. neoformans and C. gattii are lungs and central nervous system. In an immunocompromised person, cryptococcus can disseminate widely involving skin, bone/joints, prostate, and eyes. The most severe clinical manifestation of cryptococcal infection is meningoencephalitis. There are three mechanisms by which infection can spread from the lungs to brain: one, by disruption of vascular integrity leading to passive hematogenous transport; two, by endothelial cells phagocytosing spores from blood stream and later expulsing them to circulation; and three, by movement of the yeasts from the bloodstream into CNS within macrophages using the Trojan Horse mechanism. Diagnosis of cryptococcosis is based on direct visualization of the yeast, histopathology of tissue specimens, culture, and detection of cryptococcal antigen (CrAg). Cryptococcal meningitis (CM) in PLHA is associated with high mortality. Timely diagnosis and optimal therapy are both required to prevent deaths. Treatment of CM is divided into three phases: induction, consolidation, and maintenance. Three drugs have been traditionally used in the treatment of CM: amphotericin B (AmB) or liposomal amphotericin (L-AmB), fluconazole (FLU), and flucytosine (5FC). A number of strategies have been evaluated and implemented to prevent CM in PLHA with low CD4 cell counts in resource-limited settings like starting preemptive fluconazole therapy in CrAg-positive patients with low CD4 cell count.

Introduction this is a staggering 2,78,000 people. Of these, 2,23,000 Cryptococcosis is an opportunistic mycosis which was developed cryptococcal meningitis (CM) in 2014 and 73% uncommonly identified before the HIV/AIDS pandemic. of these cases occurred in sub-Saharan Africa (SSA). It is It is responsible for high mortality among people living estimated that 1,81,000 PLHA die of CM every year with 1 with HIV/AIDS (PLHA) and also among other non-HIV 75% of these deaths occurring in SSA. About 50% of PLHA immunocompromised people. The ability to detect with CM die within a year of contracting infection mainly 2 cryptococcal antigen (CrAg) has enabled us to estimate due to unsuccessful/inadequate treatment. AIDS-related the global prevalence of the infection. Cryptococcal CM causes 20–25% of AIDS-related deaths every year.3 antigenemia is prevalent in about 6% (95% confidence Cryptococcosis has been increasingly recognized in non- interval 5.8–6.2%) of PLHA with CD4 cell count <100 cells/ HIV immunocompromised people. In countries with good µL (severely immunocompromised). In absolute numbers health-care systems with equitable access to timely care,

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25% of all CM-related hospitalizations and deaths occur IRIS and mortality associated with Cryptococcal IRIS in non-HIV patients. In the US, CM is the commonest (cIRIS) varies from 0% to 67%.13-16 In HIV-negative cause of non-viral meningitis now.4 Different serotypes patients with CM, IRIS has been reported with reversal of Cryptococcus neoformans have been associated with of iatrogenic immunosuppression especially with TNF-a CM in PLHA and those without HIV/AIDS. However, the inhibitor therapy.17 IRIS has triggered a deep study of the boundaries are getting increasingly blurred now. immunobiology of HIV-associated OIs and new insights Cryptococcus is one of the four fungal species have opened up new immunomodulatory interventions. accounting for almost 90% of fungal infection related deaths in the world, the other three being Candida, Pathobiology 5 Aspergillus, and Pneumocystis. There are 37 species of C. neoformans is found in high concentrations in bird Cryptococcus in the genus Filobasidiella of the phylum guano, especially in the droppings of pigeons and chicken. Basidiomycota. Most human infections can be attributed 6 C. gattii is found in decaying vegetation especially that of to C. neoformans or Cryptococcus gatti. Based on the 7,18 the Red River gum trees (Eucalyptus camaldulensis). capsular polysaccharide, glucuronoxylomannan (GXM), Cryptococcus survives in the environment as a yeast (sexual the yeast form of Cryptococcus neoformans is classified form), producing hyphae with terminal basidiospores into four serotypes, A through D. Serotypes A and D of C. which may break off and then become aerosolized. Since neoformans are responsible for most human infections.7 their average diameter is 3 microns, they are small enough C. neoformans var. grubii (serotype A) accounts for 90% to travel right up to the alveoli. In most hosts, the infection of human infections. It is worldwide in distribution is asymptomatic. A seroprevalence study done among and is especially associated with CM in people with children in New York revealed that 70% had antibodies CD4+ T cell deficiency (mainly HIV-infected and also against cryptococcal antigens. It seems that asymptomatic in transplant recipients and those with rheumatological colonization of airways and latent infection of lungs disorders requiring immunomodulatory therapy).8,9 C. and airways maybe common.19,20 Autopsy studies have neoformans var. neoformans (serotype D) is also global in shown granulomatous lesions in lung parenchyma and distribution but is mostly identified amongst human cases 21,22 in Europe. Cryptococcus gattii (serotypes B and C) was sub-pleural nodules containing yeast forms. Just as for long thought to be a tropical/subtropical fungus but in tuberculosis (TB), a robust immune system keeps the it has now been discovered in high temperate zones like infection from manifesting as clinical disease. The most Northwestern US, Vancouver, and other parts of British severe clinical manifestation of cryptococcal infection Columbia in Canada. C. gattii causes disease among is meningoencephalitis. There are three mechanisms those with “normal” immune system. It is now also being by which infection can spread from the lungs to brain: recognized as a pathogen in PLHA, and people with other one, by disrupting vascular integrity leading to passive immunodeficiencies especially those with autoantibodies integrity leading to passive hematogenous transport, two, against granulocyte-monocyte colony stimulation factor by endothelial cells phagocytosing spores from blood (GM-CSF).10 stream and later expulsing them to circulation, and three, CM in both HIV-infected and HIV-negative with by movement of the yeasts from the bloodstream into CNS immune deficiencies is plagued by IRIS which causes within macrophages using the Trojan Horse mechanism. considerable morbidity and mortality. IRIS as a disease On crossing the blood brain barrier, the fungal cells are entity came into its own only in the course of the HIV released by vomocytosis. Just as in TB, hematogenous pandemic when highly active antiretroviral therapy spread can occur during primary infection or due to was introduced. About 10–25% PLHA without a known reactivation when immunity is lowered. Severe disease can opportunistic infection (OI) starting ART develop IRIS.11,12 develop many years after primary infection.3,23 Pirofski and Most IRIS events occur within the first 2–3 months of Casadevall proposed a mechanism which allows the host initiating ART. But delayed IRIS has been reported with to tolerate infection for long periods without manifesting cryptococcal and CMV infections and these can occur disease. They termed it the disease tolerance and damage many years later. Approximately 25% of CM patients response framework (DRF). This system mainly evolved receiving ART and antifungal therapy will develop to mitigate and avoid damage to the lungs and brain.24,25

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The DRF is based on the interplay of microbial and host a principal defense against innate immune mechanisms. factors that may either cause disease or produce a net The capsule conceals cell wall carbohydrate antigenic benefit to the host. The highly dynamic and complex epitopes, inhibits antibody binding to fungal cell wall, interaction between the fungal virulence factors and host’s and activates and depletes complement factors. The immune response can result in a variety of outcomes capsule modulates cytokine production and suppresses ranging from debilitating disease to colonization, latency T cell proliferation. It also induces apoptosis of host cells. and commensalism. Cryptococcus sp. have an array of During active infection, cryptococcal cell capsule can mechanisms that enable them to survive, proliferate, enlarge leading to formation of giant “Titan” cells. The size and disseminate in a mammalian host. The fungus of these cells varies from 50 to 100 microns and this large produces numerous enzymes which cause damage at a size inhibits phagocytosis. Fungal cells can release their molecular level. These include proteases, phospholipase, capsular glucuronoxylomannan (GXN) and this causes urease, and nuclease. At a cellular level, cryptococcus shedding of L-selectin from neutrophils. Loss of L-selectin can damage host cells by interfering with phagolysosome inhibits neutrophilic migration, endothelial adhesion, maturation, increasing permeability of phagosome and extravasation into tissues. Other capsular factors can membrane, interfering with organelle function, causing interfere with maturation and activation of neutrophils, cytoskeletal alterations, cytoplasmic vacuolation and DCs, and macrophages. The yeast cells secrete a number both lytic and non-lytic exocytosis. The first step in of enzymes that enable them to survive in the harsh the protective response against cryptococcal infection environment of the phagolysosome. These are mainly is the production of proinflammatory cytokines, then involved in nitric oxide detoxification and neutralizing followed by generation of an effective Th1/Th17 adaptive oxidative stress. Other enzymes and substances that immune response and classical activation (M1 type) of enable the fungus to survive intracellularly include urease, macrophages. All these processes lead to fungal clearance. phospholipase B1, laccase, melanin, and heat shock A robust response commensurate with fungal burden can protein70 homolog Ssal 1. The ability to escape from lead to excessive tissue damage. A good example of this host cell without causing its lysis is the most important is cryptococcal IRIS. In immunocompromised patients, mechanism for persistence of cryptococcus in host tissue. both inflammatory response and immune function are This non-lytic escape from phagocytes is also called compromised enabling unbridled fungal replication vomocytosis. This enables the organism to prevent the resulting in high fungal burden. The ideal scenario is one inflammatory response that would be associated with where the host resistance mechanisms are balanced by host cell death. Cryptococcus sp. are able to swing cellular the host tolerance mechanism. This leads to minimal/ immune response toward a non-protective Th2 response or no clinical disease and probably fungal latency. The by two main mechanisms: cryptococcal urease recruits host resistance mechanisms, namely proinflammatory immature DCs to lymphoid tissue in the lungs, and host cytokine production, activation of dendritic cells (DCs), chiotriosidase cleaves fungal chitin and triggers CD11 generation effective Th1/Th17 response, and M1 type b+ conventional DCs to undergo Th2 differentiation. macrophage polarization are balanced by cryptococcal C. neoformans secretes prostaglandin E2 (PGE2) that and host disease tolerance mechanisms. suppresses Th17 differentiation. A strong Th17 response Cryptococcus-associated disease tolerance strategies is critical for a sterilizing immune response. In fact, this can be grouped as metabolic adaptions to physiological process facilitates latent infection. conditions in the host, evasion, and interference with The host immune response to cryptococcal infection innate and adaptive immune responses. Cryptococcus can that leads to disease tolerance is due to T regulatory (Treg) activate gene expression that enables it to survive in human cells, IL-10 signaling, DC response, role of tryptophan cells at 37oC and also in nutrient-poor environments like pathway and T cell exhaustion. Tregs are involved in the the CNS. The fungus van produce meaning using host production of anti-inflammatory cytokines like IL-10, and catecholamines. This reaction is mediated by fungal transforming growth factor-β. Severe pathology occurs phenoloxidase. It is this ability to use catecholamines that when there are mutations in Treg-associated transcription gains the fungus a niche in the CNS. The capsule serves as factor fork head box protein P3 (FOXP3). CrAg-specific

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Tregs can colocalize with Th2 effector cells in infected with ART predisposes patients with CM to IRIS. Evolution lungs and thereby limit inflammatory damage. IL-10 is of cIRIS goes through three stages: pre-ART paucity an anti-inflammatory cytokine that is secreted by Tregs of inflammatory response, innate cell activation, and and DCs. It inhibits production of IL-1, Il-6, IL-23, IFN-g, immune dysregulation. During the pre-ART phase both TNF-α in fungal infections. In PLHA with cryptococcal innate and adaptive immune responses are compromised. infection, high levels of IL-10 correlate with fungemia Migration of neutrophils into the meninges and their and dissemination. Therefore, IL-10 levels can be a fungistatic activity is compromised. Poor antigenic surrogate marker of progressive or persistent cryptococcal clearance and risk for IRIS are linked to decreased levels infection. Among the antigen presenting cells, DCs are of IL-6, IL-8 and TNF-α (innate inflammatory cytokines) the ones that can present cryptococcal antigens most and IFN-g (adaptive inflammatory cytokine). Risk of cIRIS efficiently to T cells. Development of a Th1/Th17 immune increases with higher expression of CCL2 and CCL3. response greatly depends on classical activation of Natural killer cells with increased expression of CXCR3 monocyte-derived DCs (MoDCs). As mentioned earlier and CX3CR1 also participate in the initial response to capsular characteristics can affect DC activation. The cryptococcal infection in CNS. When ART is started, T local cytokine and chemokine milieu also affects their cell immunity takes some time to develop. In this interim, activation. Immunomodulatary DCs have been known to antigenic burden causes a buildup of proinflammatory evolve in the course of infection and they can lead to Th1/ signaling by antigen presenting cells. This is demonstrated Th17 suppression, reduced macrophage activation and by increased IL-6 and CRP levels in weeks preceding development of IRIS. When ART associated immune impaired fungal clearance. Indoleamine 2,3-dioxygenase restitution reaches a critical level, a powerful Th1 response (IDO) is an enzyme involved in tryptophan metabolism. and cytokine storm herald the onset of IRIS. Phagocytic It plays an important role in balancing the activity of Tregs killing of intracellular pathogens is also defective due to and Th1/Th17 cells. Expression of IDO by DCs leads to a absence of IFN-g signaling from CD4 T cells in the pre- tolerogenic phenotype in experimental models. The same ART phase. But a buildup of partially primed myeloid has not been demonstrated in humans with cryptococcal cells occurs in the CNS during this time. When CD4+ cell infection. Its significance is still to be explored. A reconstitution occurs with ART, activation of these myeloid state of chronic immune activation can lead to T cell cells with production of proinflammatory cytokines exhaustion. One of the mechanisms that promotes this occurs. Myeloid cells that accumulate in CNS prior to IRIS is the upregulation of cytotoxic T lymphocyte-associated are mainly proinflammatory intermediate monocytes. The protein-4 (CTLA-4). T cell activation and function depend final phase of IRIS is marked by immune dysregulation. In on a double signal: the binding of antigen presented by a normal response to a fungal infection classical activation MHC to T cell receptor and binding of CD80 and CD86 on of monocytes leads to increased fungal kill. However, this anitigen-presenting cell to CD-28 on T cell. CTLA-4 binds does not occur in immunocompromised people. Here to CD80 and CD86 and thus blocks CD-28. In the absence the buildup is of intermediate monocytes with increased of this co-stimulatory signal T cells become anergic. In expression of programmed death ligand-1 (PD-L1). Their murine cryptococcal infection models, upregulation of activity results in a powerful inflammatory response CTLA-4 has been demonstrated. Sustained expression and less efficient fungal kill. Lymphopenia associated of programmed cell death protein-1 (PD-1) on CD4 with HIV infection results in a homeostatic response to T cells, DCs and macrophages is also associated with cryptococcal infection regulated by IL-6 and characterized persistence of infection. Modulation of levels of CTLA-4 by proliferation of naive T cells which resemble effector and PD-1 could be strategies for treating cryptococcal IRIS memory T cells. Later, during IRIS, these cells ramp up 4,26,27 (cIRIS). secretion of IFN-g and push the immune activity toward a powerful Th1 response. Immune restitution also results Cryptococcal IRIS in a robust increase of highly-differentiated memory T cell depletion in HIV infection severely compromises CD4+ T cells with no inhibitory control. The net result is adaptive immune response and this can lead to unbridled severe inflammation, tissue destruction, and functional fungal dissemination to the meninges. Immune restitution impairment.28-32

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Clinical Features immunocompetent person without CNS symptoms. Here, infection can be presumed to be limited to the lungs. The preferred sites of infection by C. neoformans and C. gattii are lungs and CNS. In an immunocompromised Central Nervous System person, cryptococcus can disseminate widely. They can involve skin, bone/joints, prostate, and eyes. A The presentation of CM is usually subacute with symptoms retrospective study of cryptococcosis in Denver, Colorado, developing over weeks. Clinical symptomatology may USA, showed that patients with cryptococcosis had, apart include fever, lassitude, headache, altered sensorium, from features of CM, respiratory symptoms, hyponatremia, and focal deficits like cranial neuropathies. In severely prior lung disease, or history of corticosteroid therapy.33 immunocompromised patients, fungal burden in the CSF can be very high (>1 million yeast cells/mL of SF). In Respiratory System these patients presentation is usually acute and features of raised intracranial pressure maybe present. Their CSF will The main route of entry of cryptococcus is through the also show high CrAg titers. A study from SSA showed that respiratory tract. Clinical manifestations are varied and seizures occurred at presentation in 28% (231/821) HIV depend on immune status. In an immunoscompetent positive subjects with CM and 15.5% developed seizures person it can be just a symptomless colonization of the during the course of illness. Seizures at presentation were airways or a pulmonary nodule detectable only on a associated with lower GCS scores, lower CD4 cell counts radiograph. In the immunocompetent, the infection is increased CSF opening pressures when compared to HIV+ accidentally discovered on imaging in up to one-third patients with CM but without seizures. CSF fungal burden of the cases. The radiological manifestation maybe a was higher in those with seizures at presentation than in solitary nodule or multiple nodules without calcification those developing seizures during course of illness.37 C. or pulmonary infiltrates. Hilar lymphadenopathy, gattii infections can cause cryptococcomas in the brain pleural effusion, and cavitary lesions are also described. and can also cause obstructive hydrocephalus. In the The presentation is more florid and dangerous when lungs also it can cause mass lesions. Focal neurological the immune system is compromised. In this setting deficits and cranial neuropathies due to cryptococcomas the manifestation can be a severe pneumonia or a are common manifestations. These patients respond life-threatening acute respiratory distress syndrome poorly to antifungal therapy and decompressive surgery 34,35 (ARDS). Isolated pulmonary cryptococcosis can may be required to relieve raised ICP. C. neoformans is less occur in the absence of CNS involvement in the likely to cause such lesions.38-40 immunocompromised. In the presence of cryptococcal In the absence of a definite microbiological diagnosis, meningoencephalitis, pulmonary involvement is seen TB meningitis (TBM) is the commonest differential in 10–55% of PLHA. But here, neurological symptoms diagnosis for CM. In both, fever, headache, and vomiting 35 usually dominate. A Chinese study in HIV-negative are common presenting complaints. Altered mental status subjects reported slightly different findings. In this study, is more common in CM than in TBM in HIV-negative 49.3% of the subjects with CM had evidence of pulmonary individuals. Altered vision and hearing are commoner in cryptococcosis. They usually presented with fever, cough, CM and cough is more likely in TBM. CM is associated with expectoration, and lower limb edema rather than with corticosteroid use, pulmonary infection, hepatobiliary CNS symptoms. Subjects with lung infection were also disease and diabetes. Those with TBM are likely to have younger (<30 years) than those who did not have lung TB elsewhere outside CNS or disseminated TB.36,41 In infection.36 Serum CrAg is usually negative in truly isolated the Denver study, risk factors associated with CM were pulmonary cryptococcosis. Whenever cryptococcus is HIV infection, prior use of corticosteroids, malignancy, isolated from the lungs or other sterile body sites in an transplant status, lung disease, and active smoking.33 immunocompromised individual, a lumbar puncture In HIV negative children with CM, fever, nausea, to exclude CNS disease is recommended regardless vomiting, and headache are the commonest symptoms. of the patient’s symptoms or serum CrAg titer results. Meningeal signs, altered consciousness, and fundal The only exception for a diagnostic LP would be an changes are common findings. CSF opening pressure is

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raised in most. Involvement of other organs is common cryptococcosis another entity is described and that is with the lungs being the commonest.42 post-infectious inflammatory response syndrome which is Among the elderly, those older than 65 years are a clinical deterioration in a previously healthy individuals. more vulnerable to developing CM. There is a female All of them also have an exaggerated anti-cryptococcal preponderance and altered consciousness and cerebral immune response. Cryptococcal IRIS causes severe infarction are more common than in the young.36 morbidity and is associated with a high mortality.14,45-47 Cryptococcal IRIS is a diagnosis of exclusion. Progressive Skin infection secondary to suboptimal antifungal therapy, After pulmonary and CNS involvement, cutaneous primary antifungal drug resistance or persistent immune manifestations are the commonest presentation of deficits, other coexistent OIs (like TB), malignancy, cryptococcosis. Usually the lesions are non-specific and drug toxicity need to be excluded. Risk factors for and similar to those seen in other infections. Primary IRIS include severe immune deficiency at baseline with cryptococcosis is uncommon and is due to direct rapid immune restitution with ART, high fungal burden inoculation of the fungus into the skin by injury at baseline and ineffective immune repose in the host or laboratory accidents. The lesions are single and during initial infection. The commonest time period for occur at the site of innoculation. They can present as cIRIS is within first 3 months of starting ART. Classical whitlow, papule, nodule, ulcerated lesion or cellulitis. In features of cIRIS in HIV infected patients with low CD4 immunocompromised patients, dermal cryptococcosis cell counts include little or no meningeal irritation is secondary to disseminated infection. Here the lesions despite high cryptococcal load, extremely high serum and tend to be multiple. Lesions often resemble those of CSF CrAg tiires, muted inflammatory response in CSF molluscum contagiosum. They are flesh-colored papules/ manifesting as low CSF WBC count, and high yeast burden on CSF microscopy and ease in culturing yeast from CSF nodules with central umbilications. Pustules, acneiform 48 lesions, abscesses, cellulitis, and gralulomata have or serum. all been described. Regional lymphadenopathy and discharging sinuses may occur. Skin biopsy and cultures Laboratory Diagnosis are required to culture and identify the fungus. Solid Diagnosis of cryptococcosis is based on direct visualization organ transplant recipients on tacrolimus are prone to of the yeast, histopathology of tissue specimens, culture, cutaneous cryptococcosis and osteoarticular involvement. and detection of CrAg. Molecular methods, although Tacrolimus inhibits a protein required for cryptococcal available and extensively used for research purposes, are growth at 37°C. It acts by interfering with calcineurin not used currently in routine clinical practice. signaling pathway in the fungus. However, at lower Direct visualization is traditionally by India ink temperatures (<24°C), this inhibitory activity is lost staining. The fungus appears as a globular, encapsulated making patients on calcineurin inhibitors prone to yeast cells which may or may not be budding. The yeast cryptococcal infection.43,44 cell size varies from 5 to 20 μm in diameter. India ink staining is the most rapid method for diagnosis of CM and Immune Reconstitution Inflammatory Syndrome has been the method in vogue in low-income countries Antiretroviral therapy leads to immune restitution for a long time. The sensitivity is only 80–85% for AIDS- in PLHA. When this process occurs in a severely related CM, meaning that 1 in 7 diagnoses will be missed. immunocompromised person, it leads to a rebound of Sensitivity falls to about 40% in patients with low fungal pathogen-specific immunity. This manifests as a clinical burden (<1,000 CFUs/mL of CSF). Detection of yeasts is entity called immune reconstitution inflammatory operator dependent. Lysed WBCs can be mistaken for 49,50 syndrome. When there is a “paradoxical” deterioration fungal elements. of a known OI or appearance of the OI in new sites or “recurrence” of OI while on ART, it is called paradoxical Histopathology IRIS. In unmasking IRIS, ART leads to an accelerated Cryptococcus can be detected from a variety of tissue manifestation of an occult infection. In the context of samples like lungs, brain, skin, bone marrow, lymph nodes,

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and other organs.51 Histopathology is more sensitive than EIA had a lower sensitivity for serotypes C and D. False India ink staining. Special staining techniques are available positive test results are low but known (<1%). These are to visualize different fungal elements. Mucicarmine, due to technical issues, contamination or infection with Alcian Blue, and Periodic-acid-Schiff stain the fungal Trichosporon beigelli, Capnocytophaga canimorsus, and polysaccharide capsule. The melanin in the yeast cell Stomatococcus mucilaginosus. False negatives can be wall is delineated by Fontana–Masson stain. Gomorri- seen early in infection due to a low fungal burden, due methenamine-silver stain also enables visualization of the to poorly encapsulated organisms and due to prozone cell wall. Calcofluor binds to fungal chitin.52,53 effect in the setting of extremely high antigen titers, which can be overcome with dilution.58 False-negative results in Culture latex agglutination tests can occur in the early stages of Cryptococcus can be cultured readily using routine fungal infection when fungal burden is low and also because of 49,52,54,59 or bacterial culture media. CSF, sputum, and skin biopsy improper storage of clinical sample. sample all yield the fungus easily. The sensitivity of CSF The US FDA has approved a lateral flow immuno­ and blood cultures in adult PLHA with CM is 90% and chromatographic dipstick assay (LFA) for serum and CSF. 50–70% respectively. Volume of inoculum determines the The European Union has approved it for serum, plasma, culture sensitivity. It is 82% for 10 µL of CSF and 94% for and CSF. It can detect CrAg of all species of cryptococcus. 100 µL.54,55 Fungal culture remains relevant even today The test uses a combination of two monoclonal antibodies. for clinical, therapeutic, and research reasons. For the The first one is reactive one against CrAG of serotypes clinician, cultures help confirm clearance of the yeast from A, B, and C. The other is highly reactive against CrAg of CSF after induction therapy, and to distinguish between serotypes A and D. The test can be done in five easy steps relapse of CM and paradoxical IRIS. Serial cultures have a (as shown in Fig. 1) and and takes 10 minutes to give the log 10-linear clearance. This enables computation of early result. The test meets the World Health Organization’s fungicidal activity (EFA). EFA is a useful marker of drug (WHO) “ÁSSURED” çriteria. It is affordable (i.e., cheap), regimen potency and is also used as an efficacy endpoint sensitive (equal to or better than other CrAg tests), specific in phase II trials. Quantitative cultures allow measurement (similar to other CrAg tests), user-friendly (just as easy of fungal colony forming units (CFUs) from CSF. The as the pregnancy test), rapid and robust (done in 10 disadvantages of using culture for diagnosis are that minutes), equipment-free, and delivered (i.e., it is portable results become available only in 3–7 days, and in a setting and light-weight with a long shelf-life and requiring no of low fungal burden, cultures can be negative.56 refrigeration). CrAg LFA can be used both qualitatively and Serology semiquantitatively. A schematic representation of CrAg Serological tests to detect cryptococcal capsular antigen LFA is shown in Figures 2A and B. The test has been has made diagnosis of cryptococcal infection easy and validated in a large muticentric study in South Africa fast. CrAg has been detected in CSF and serum using latex and Uganda. The test has a sensitivity and specificity agglutination and enzyme immunoassay (EIA) techniques of 99.3% and 99.1% respectively. The data provided by for more than two decades. The sensitivity of CrAg-Latex the manufacturers state that LFA has a sensitivity and for serum and CSF is 83–97% and 93–100%, respectively. specificity of 99.5% and 99% respectively and, positive The specificity for serum and CSF is 93–100% and 93–98%, predictive and negative predictive values of 98% and of respectively. For EIA, the sensitivity for serum and CSF is 99.7% respectively with serum, plasma, urine, or CSF 94% and 100% respectively and the specificity is 96% and samples when compared to cultures. There is 100% 98% respectively.55,57 Both CrAg-Latex and EIA have some concordance for serum and plasma tested by fingerstick disadvantages. The CrAg-Latex is a manual test and there LFA test and 100% negative predictive value for excluding is a high degree of subjectivity in its interpretation. Both CM. The finger stick LFA can show false negative result require laboratory infrastructure, and refrigeration of in a scenario of asymptomatic patient with a low fungal reagents thereby making the tests expensive. CrAg-Latex burden. Pipetting whole blood on to the LFA can increase has lower sensitivity for CrAg of serotype C (C. gattii). diagnostic yield over direct application of blood to CrAg

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Fig. 1: Five easy steps to detect cryptococcal antigen using LFA. Step 1: add one drop of specimen to a tube. Step 2: add of 40 μL (1 drop) of patient specimen to the tube. Step 3: insert the LFA strip into the tube. Step 4: incubate for 10 minutes. Step 5: interpret results60

Figs. 2A and B: (A) Schematic representation of lateral flow immunochromatographic assay for detection of CrAg. (B) Images of positive and positive and negative controls61

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LFA sample pad.62 CrAg LFA is about 5 times more sensitive in Uganda at risk of cryptococcal disease. Screening than CrAg-Latex when comparing semi-quantitative titers them and pre-emptively treating 15,500 people with by serial dilution. This means that a specimen positive fluconazole would cost $822,600 which is 15% cost of by CrAg-Latex at 1:8 dilution will be positive by CrAg LFA treating meningitis that would occur otherwise. It would at 1:40 dilution. The semiquantitative assay reports the also lead to 40% better long-term survival.64 The low highest dilution that gives a positive result. cost of LFA makes screening for CrAg compellingly cost- CrAg detection is used for detecting early CM, screening effective even in areas of prevalence as low as 1%. WHO PLHA for cryptococcal infection, and for prognostication recommends screening of all ART-naive PLHA with CD4 and therapeutic decision-making (when it is done semi- cell count <100/µL for cryptococcosis by CrAg testing in quantitatively). serum/plasma. It also recommends antifungal therapy if CrAg is positive to prevent development of disease. Detection of Early Cryptococcal Meningitis A study in Uganda investigated 1201 HIV positive CrAg Titer individuals hospitalized for suspected meningitis. Fifty-six Semi-quantitative estimation of antigenemia can be percent of these patients (671/1,201) had CM confirmed done by both CrAg-Latex and LFA by serial dilution by CSF CrAg positivity. Four percent of the subjects with titers. Unfortunately the test is not standardized and neurological symptoms and CSF analysis negative for CrAG results can vary with kits from different manufacturers. were found to have serum CrAg positivity. Cryptococcus The variability is more for the latex test. The CrAg LFA was identified by culture or PCR in 9% of these serum manufactured by IMMY is considered the gold standard CrAg+ and CSF CrAg- patients. This subset of patients diagnostic.56 Semi-quantitative assays are clinically useful with neurological symptoms, serum CrAg positivity, and because antigenic titers correlate with disease severity and CSF CrAg negativity constitute the early cryptococcal mortality. Plasma/serum CrAg titers of <1:80 are unlikely meningo-encephalitis’ group. In-hospital mortality was to be associated with CNS disease. The probability of 32% in symptomatic cryptococcal antigenemia and 31% CNS involvement increases beyond a titer of 1:160 and in CM. These findings suggest that immunocompromised there is near-universal concordance with CNS disease patients with suspected CNS infections should always at titers of 1:1,280. It is suggested that laboratories run have serum tested for CrAg especially when no CSF test at two dilutions, namely 1:160 and 1:1,280. This pathogen is detected and that in early cryptococcal will enable risk stratification of patients into low risk meningoencephalitis, yeasts maybe present in brain (<1:160), intermediate risk (1:160 to 1:1,280) and high risk 63 parenchyma without meningeal involvement. (>1:1,280) of infection. All those in high risk group should be considered to have disseminated disease regardless Screening for CrAg of symptoms.10 Rajasingham and colleagues pooled data CrAg appears peripheral blood many weeks to months from four cohorts and found that survival decreased as before the onset of symptomatic disease. There is thus an plasma CrAg titer increased from <1:160 to >1: 2,560 (log opportunity for early detection and pre-emptive action. rank P <0.0001). Worryingly, mortality rates were high in Serological prevalence studies for CrAg in PLHA have asymptomatic individuals with CrAg >1:160 despite their been done in various parts of the world. The serological receiving pre-emptive fluconazole therapy.1,50,65 prevalence of CrAg in ART-naive asymptomatic PLHA Programmatic challenges exist to screen severely with CD4 cell count <100/µL is 6.8% (95% CI: 2.2–21%) immunocompromised PLHA for CrAg. The strategy of and 4–12.9% in Africa and Southeast Asia respectively. ordering the test for people who have got a CD4 count In Brazil, the prevalence in hospitalized PLHA with CD4 report of <100/µL is not efficient and many patients will cell count <200/µL is 3.1% and 11.4% in two different miss the test. This is known as the “provider-initiated studies. The global average prevalence in severely testing” strategy. A study from South Africa showed that immunocompromised PLHA is 6%. The mathematics of only 27% of those eligible actually got screened by this cryptococcal screening for PLHA has been worked out. strategy.66 It also increases the work of the clinic staff There are 110,500 severely immunocompromised PLHA because they have to raise another investigation form

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and draw another blood sample. The best strategy that ART-experienced patients. Timely diagnosis and optimal has evolved is one known as “reflexive screening.” Testing therapy are both required to prevent deaths. Treatment of for CrAg is a part of the laboratory protocol. Whenever CM is divided into three phases: induction, consolidation, the laboratory finds a CD4 test result of <100/µL, it will and maintenance. The induction phase is meant to automatically run the CrAg test on the remaining blood drastically reduce fungal burden in the CSF within 2 weeks sample. The laboratory will also report it in along with the and is critical for good outcomes. Three drugs have been CD4 count result and will also offer a brief explanation as traditionally used in the treatment of CM: amphotericin B to what to do with a positive CrAg report. (AmB) or liposomal amphotericin (L-AmB), fluconazole (FLU), and flucytosine (5FC). Of these FLU is the cheapest Other Tests and most widely available drug. FLU monotherapy, even 1-3β-D Glucan (BDG): It has been long believed that the highest doses, is associated with high mortality (50% 69 Cryptococcus does not produce enough BDG to be during 10 weeks of treatment). Various 2-week induction detected easily. A study done in Africa showed that BDG regimes have been tried. The main aim was to reduce the can be detected in the CSF of PLHA with CM with a serious adverse effects (SAEs) associated with AmB. The sensitivity and specificity of 89% and 85% respectively. dose and duration of therapy have both been modified in Sensitivity increases to 98% when fungal burdens are high various studies. For a long time AmB 1 mg/kg/d + 5FC 100 (>10,000 CFUs/mL). Unlike CrAg, BDG levels decline fast mg/kg/d for 14 days was accepted as standard induction with treatment and thus and thus it can potentially be used therapy for HIV-associated CM. But delivering a 2-week to monitor therapy, detect relapse, and also differentiate course of AmB remains a challenge due to SAEs, and cost. relapse from cIRIS.67 Phase II trials have demonstrated that a shorter course of Uses of film array system of multiplex PCR have been AmB is associated with fewer SAEs than a 2-week course tried for detecting common pathogens causing meningitis. without reduction in rates of fungal clearance by 2 weeks. 70,71 Cryptococcal infection can be detected with a sensitivity of This is attributed to long half-life of AmB in the brain. 96% when fungal burden is high (>100 CFUs/mL of CSF) The Advancing Cryptococcal meningitis Treatment for but only with a sensitivity of 50% at low fungi burdens Africa (ACTA) trial looked at survival rates at day 14 and (<100 CFUs/mL of CSF). The high cost and sophisticated day 70 of a 1 week course of AmB combined with either laboratory facilities preclude its widespread use. high dose FLU or 5FC, 2 weeks of oral therapy with 5FC Ribosomal DNA genes and their internal transcribed and high-dose FLU and 2 week AmB combinations. The spacers (ITS) have been found to be a good common study showed that 1-week combination of AmB and 5FC marker for bacteria and fungi. It is possible to detect inter- had the lowest 10-week mortality of all regimens and that and intra-specific variations. Deep sequencing of rDNA 5FC was superior to FLU as a partner drug to AmB (10 72 amplicons from CSF can diagnose CM. Metataxonomics week mortality HR 0.62, 95% CI: 0.45–0.84, p=0.0020). of ITS amplicons may be the test of the future for rapid A systematic review and meta-analysis has looked at diagnosis and genotypic recognition of Cryptococcus sp.68 data from 13 studies with 2,426 patients. It found that at 10 weeks a 1-week course of AmBd plus 5FC was superior to other regimes for induction treatment of HIV- Treatment associated CM. In the case of non-availability of AmB Cryptococcal meningitis in PLHA is associated with high a combination of 5FC and high-dose FLU was the next mortality. Some strategies to decrease morbidity and best alternative.73 These two regimens have now been mortality include: early diagnosis of HIV infection and accepted as the standard first-line treatment regimens early initiation of ART; ART adherence and retention by WHO for HIV-associated CM. The standard WHO in care; CrAg screening and treatment approach; and recommended treatment regimen for HIV-associated CM improved CM care. is shown in Table 1. The alternate regimens that can be Despite the global coverage of ART being about 60%, used during the induction phase are: 5FC + high-dose FLU CM remains a therapeutic challenge. The incidence of CM for 2 week or AmB + high-dose FLU for 2 weeks (high-dose remains high and more than 50% of CM cases occur in FLU=1,200 mg/d).

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TABLE 1 WHO-recommended first-line antifungal therapy for treatment of cryptococcal meningitis

Medication and dose Week 1 Week 2 Week 3 - 10 AmB (1.0 mg/kg/d) + 5FC 100 mg/kg/d Xa FLU 1200 mg/d X FLU 800 mg/d X FLU 200 mg/d Through 12 months Treatment phase Induction Consolidation Maintenance aTherapeutic lumbar puncture and electrolyte supplementation are most critical during the first week of therapy.74

Efforts to further shorten AmB exposure and thus can do more harm than good. IRIS occurs in 15–20% cut down on cost and minimize SAEs are on. L-AmB is patients initiating ART. The Cryptococcal Optimal ART associated with fewer SAEs than AmB. The AMBITION Timing Trial (COAT) provided some definitive guidance trial was a phase II trial looking at efficacy of different doses to delaying initiation of ART in patients with CM for a and durations of L-AmB in treatment of CM. L-AmB in a minimum of 4 weeks after starting antifungals. This trial dose of 3 mg/kg/d and FLU 1,200 mg/d were administered demonstrated improved survival in patients with CM in for 14 days in the induction phase in the control arm. This whom ART initiation was deferred for up to 5 weeks after was compared with LAmB 10 mg/kg on D1 and 5 mg/kg diagnosis as compared with immediate ART (within 1–2 on D3 + FLU 1,200 mg/d for 14 days; LAmB 10 mg/kg/d weeks).29 A Cochrane Review further concluded that there on D1 + 5 mg/kg on Ds 3 and 7 + FLU 1,200 mg/d for 14 is higher all-cause mortality if ART is initiated early in days and LAmB 10 mg/kg on D1 with FLU 1,200 mg/d for CM in HIV-infected people in low- and middle-income 14 days. The primary outcome was early fungicidal activity countries.78 The 2018 WHO guidelines recommend that and it was non-inferior in all the three short course arms ART should be started 4–6 weeks after starting antifungal as compared to the control arm. The mortalities in all arms treatment. were comparable. Encouraged by its results, AMBITION II phase III trial has been rolled out. This study compares the Newer Adjuvant Therapies for Treatment of CM new WHO first-line regimen of AmB 1 mg/kg/d + 5FC 100 Sertraline, tamoxifen, INF- , and steroids have all been mg/kg/d for 7 days followed by high-dose FLU 1,200 mg/d tried. Steroids are associated with slower fungal clearance for 7 more days with a single dose of L-AmB 10 mg/kg on and increased mortality and are thus not recommended. day 1 along with 14 days of 5FC and high-dose FLU. The Sertraline adjunctive therapy led to faster CSF cryptococcal 75 results will be out in mid-2021. clearance, and decreased IRIS and relapses when compared to historical data.79,80 Neurapheresis is the extra- Management of Raised Intracranial Pressure corporeal filtration of yeasts from CSF in CM. A proof-of- An intracranial pressure of >250 mm of water is associated concept study in murine models has demonstrated its with poor short-term survival in patients with CM.76 efficacy. Human trials have not been encouraging.81,82 Repeated lumbar punctures improved survival in the COAT study.29 The raised ICP is due to a strong inflammatory Newer Drugs response in the CNS. Though dexamethasone is known Flubendazole is an imidazole anti-parasitic drug. It acts to decrease levels of TNF-α, it also decreases the rate of against cryptococcus by binding to fungal tubulin. Though 77 fungal clearance and causes poor outcomes. It is thus studies in mice were encouraging, the results in rabbit contraindicated in treatment of CM. studies were disappointing due to poor CSF penetration. An oral formulation is under development and could still Advances in Initiating ART in PLHA with CM serve as an adjunctive therapy.83 VT1129 is a tetrazole Cryptococcal meningitis signals a severely immuno­ which has also demonstrated in vitro activity against both compromised state in PLHA. But starting ART precipitately susceptible and FLU-resistant cryptococcal species. It

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acts by inhibiting fungal cytochrome P450 enzyme Cyp51 CD4 count <100/µL are regularly started on ART and are thereby inhibiting biosynthesis of ergosterol. The unique CrAg negative, primary prophylaxis with FLU offers no feature of this drug is its high selectivity for fungal enzyme mortality benefit and may not be necessary.94 Primary and thus its lack of SAEs and drug interactions.84 Some anti-cryptococcal prophylaxis is not recommended in more exciting drugs are under clinical trials and results high-income regions like Europe and the USA, where ART should be out in 2021. These include an orally bioavailable is widely available and CrAg prevalence in population is form of AmB, and a glycophosphatidylinositol-anchored low.95 There is some data that “screen and treat” would wall transfer protein (G wt 1) inhibitor which inhibits be cost-effective, even in resource-rich settings, although transfer of mannoprotein from the golgi complex to cell this is currently not part of standard practice.96 Another wall.56 vexing issue that has risen because of the widespread use of primary prophylaxis for CM in Africa is that of emerging Prevention fluconazole resistance in Uganda.97 A number of strategies have been evaluated and Secondary Chemoprophylaxis implemented to prevent CM in PLHA with low CD4 cell Suppressive or maintenance therapy is offered to all CM counts in resource-limited settings. A widely accepted patients on completion of intensive and consolidation one is the “screen and treat” approach. Here, serum phases of treatment because relapse rate of CM is 50% CrAg testing is used to decide on starting preemptive in the first year.98 Fluconazole at 200 mg daily is the fluconazole therapy in CrAg-positive patients. Fluconazole suppressive therapy of choice. WHO recommends is administered in a dose of 400 mg BD for 2 weeks followed continuing till CD4 count rises to more than 200/µL. IDSA by 400 mg OD for 6 weeks. It is continued at a dose of 200 recommends that suppressive therapy can be stopped mg OD till CD4 cell count rises to >200 cells/µL.85 This after 12 months if CD4 count is more than 100/µL and approach is associated with a decreased incidence of CM there is virological suppression sustained for >3 months and improved survival among those with advanced HIV (undetectable or very low viral RNA). Therapy should be disease. It has been successfully implemented in several restarted if CD4 dips below 100/µL.99 resource-limited settings, with a baseline prevalence of asymptomatic cryptococcal antigenemia of 5–13%.86-88 The cost saving and survival benefit of screen and treat strategy Outcomes has been validated by many studies when compared with HIV associated CM has a 3-month mortality of 70% in standard of care or universal fluconazole prophylaxis, Africa. The major risk factors for mortality are: longer even at CrAg prevalences of as low as 0.6%.89,90 The WHO duration of symptoms, altered mental status, concomitant recommends implementation of CrAg screening and cryptococcal lung infection, disseminated disease, high preemptive fluconazole therapy in ART-naive adults with fungal burden with low rate of clearance, low CSF WBC a CD4 count <100/µL before initiating ART in endemic count (<20 × 106/mm3, raised ICP on admission and lack settings.91 This strategy has been incorporated into existing of facilities to perform therapeutic lumbar puncture (LP) HIV-care programs of many countries in sub-Saharan to control ICP and abnormal brain imaging. Mortality is Africa. It has been shown that fluconazole monotherapy higher in low- and middle-income countries than in high- is inadequate to prevent CM deaths in asymptomatic income countries because of the high proportion of late CrAg positive with undiagnosed cryptococcosis. This testers and late presenters, CM being the presenting illness is because fluconazole monotherapy is suboptimal for in HIV disease, severe immunosuppression compounded treatment of CM. In all asymptomatic CrAg positive PLHA, by anemia, malnutrition, delayed diagnosis due to lack every effort should be made to diagnose cryptococcosis. of optimal laboratory services, non-availability of good Investigations should include CSF examination and blood combination antifungal therapy and lack of facilities for cultures. A suggested approach is to give combination therapeutic LP.10,36 The study from the USA showed that antifungal therapy for all CrAg positive patients or at least seizures in HIV+ patients with CM were associated with those with CrAg >1:160.92,93 A Thai study showed that in increased 10 week mortality ( adjusted hazard ratio 1.45, settings where ART is widely available and PLHA with 95% CI: 1.11–1.89). Patients with seizures also had more

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cognitive deficits after 3 months when compared to those . 3 Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the without seizures.37,100 TB confection with CM is associated current global burden of cryptococcal meningitis among persons with an increased hazard of death (HR 1.75, 95% CI: 1.33– living with HIV/AIDS. AIDS. 2009;23(4):525-30. 101 4. Elsegeiny W, Marr KA, Williamson PR. Immunology of cryptococcal 2.32, p<0.001). infections: developing a rational approach to patient therapy. Front A study from Uganda and South Africa showed that of Immunol. 2018;9:651. the estimated hazard of death at 18 weeks was 10% lower . 5 Brown GD, Denning DW, Gow NA, et al. Hidden killers: human for every 50 cells/µL increase in absolute CD4 cell count fungal infections. Sci Transl Med. 2012;4(165):165rv13. at the time of diagnosis. Mortality was lowest when CD4 . 6 Maziarz EK, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2016;30(1):179-206. cell count was between 50–99 cell/µL (mortality 35%) and . 7 Hajjeh RA, Brandt ME, Pinner RW. Emergence of cryptococcal higher if CD cell count was <50 cell/µL (47%) or if it was disease: epidemiologic perspectives 100 years after its discovery. >100 cell/µL (40%). These findings were consistent with Epidemiol Rev. 1995;17(2):303-20. the DRF theory.102 . 8 Singh N, Dromer F, Perfect J, et al. Cryptococcosis in solid organ Cryptococcal antigenemia has a strong association transplant recipients: current state of the science. Clin Infect Dis. 2008;47(10):1321-7. with CM/mortality in PLHA with cryptococcosis and CD4 . 9 Hage CA, Wood KL, Winer-Muram HT, et al. Pulmonary cell count between 100–200 cells/µL (Hazard ratio 10, 95% cryptococcosis after initiation of anti-tumor necrosis factor-alpha CI: 2.2–45.3, p=0.003).103 A high fungal burden of >100,000 therapy. Chest. 2003;124(6):2395-7. CFUs/mm3 is also associated with increased mortality.56 10. Vidal JE, Boulware DR. Lateral flow assay for cryptococcal antigen: The outcome of CM is bad even in Latin America. In one 15 an important advance to improve the continuum of HIV care and reduce cryptococcal meningitis related mortality. Rev Inst Med year-follow up study, with 340 enrolled patients, 42% died Trop Sao Paulo. 2015;57(Suppl 19):38-45. during follow-up. More deaths were seen after starting 11. Lederman MM, Valdez H. Immune restoration with antiretroviral ART than in treatment naive HIV-CM.104 Another study therapies: implications for clinical management. JAMA. from the USA showed that CM led to hearing impairment, 2000;284(2):223-8. muscle weakness, and cognitive deficits.33,34 12. Murdoch DM, Venter WD, Feldman C, et al. Incidence and risk factors for the immune reconstitution inflammatory syndrome in In elderly patients, mortality directly correlates with HIV patients in South Africa: a prospective study. AIDS. 2008;22(5): age (>65 years). The presence of cryptococcaemia is the 601-10. most significant prognostic factor in these people.105 13. Jenny-Avital ER, Abadi M. Immune reconstitution cryptococcosis after initiation of successful highly active antiretroviral therapy. Clin Inf Dis. 2002;35(12):e128-33. Conclusion 14. Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution Cryptococcal disease in PLHA continues to be a big public inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr. 2009;51(2):130-4. health problem in low and middle income countries. Routine 15. Boulware DR, Meya DB, Bergemann TL, et al. Clinical features and CrAg screening and pre-emptive antifungal therapy, can serum biomarkers in HIV immune reconstitution inflammatory significantly reduce CM associated morbidity and mortality in syndrome after cryptococcal meningitis: a prospective cohort these regions. Exclusion of cryptococcosis in asymptomatic study. PLoS med. 2010;7(12):e1000384. PLHA with advanced disease and high CrAG titers is a good 16. Achenbach CJ, Harrington RD, Dhanireddy S, et al. Paradoxical strategy. Combination antifungal therapy has made a immune reconstitution inflammatory syndrome in HIV-infected significant difference in outcome of HIV-associated CM. The patients treated with combination antiretroviral therapy after AIDS- regimes are becoming more affordable, shorter, and safer. cIRIS defining opportunistic infection. Clin Inf Dis. 2012;54(3):424-33. continues to be a problem in immunocompromised persons 17. Marie I, Guglielmino E. Non tuberculous anti-TNF associated with cryptococcosis. opportunistic infections. La Revue de medecine interne/fondee par la Societe nationale Francaise de Medecine Interne. 2010;31:353-60. 18. Emmons CW. Saprophytic sources of Cryptococcus neoformans associated with the pigeon (Columba livia). Am J Hyg. 1955;62(3): References 227-32. . 1 Rajasingham R, Smith RM, Park BJ, et al. Global burden of HIV- 19. Davis J, Zheng WY, Glatman-Freedman A, et al. Serologic evidence associated cryptococcal meningitis: an updated analysis. Lancet of regional differences in paediatric cryptococcal infection. Pediatr Infectious Diseases. 2017;17(8):873-81. Infect Dis J. 2007;26(6):549-51. . 2 Williamson PR. The relentless march of cryptococcal meningitis. 20. Nadrous HF, Antonios VS, Terrell CL, et al. Pulmonary cryptococcosis Lancet Infect Dis. 2017;17(8):790-91. in non-immunocompromised patients. Chest. 2003;124(6):2143-7.

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21. Salyer WR, Salyer DC, Baker RD. Primary complex of Cryptococcus 40. Mitchell D, Sorrell T, Allworth A, et al. Cryptococcal disease of and pulmonary lymph nodes. J Infect Dis. 1974;130(1):74-7. the CNS in immunocompetent hosts: influence of cryptococcal 22. Baker RD, Haugen RK. Tissue changes and tissue diagnosis in variety on clinical manifestations and outcome. Clin Infect Dis. cryptococcosis; a study of 26 cases. Am J Clin Pathol. 1955;25(1): 1995;20(3):611-6. 14-24. 41. Qu J, Zhou T, Zhong C, et al. Comparison of clinical features and 23. Rohatgi S, Pirofski LA. Host immunity to Cryptococcus neoformans. prognostic factors in HIV-negative adults with cryptococcal Future Microbiol. 2015;10(4):565-81. meningitis and tuberculous meningitis: a retrospective study. BMC 24. Pirofski LA, Casadevall A. The damage-response framework of Infect Dis. 2017;17:51. microbial pathogenesis. Nat Rev Microbiol. 2003;1(1):17-24. 42. Guo L, Liu L, Liu Y, et al. Characterisitcs and outcomes of cryptococcal 25. Pirofski LA, Casadevall A. The damage-response framework as a meningitis in HIV seronegative children in Beijing, China 2002-2013. tool for the physician-scientist to understand the pathogenesis of BMC Infect Dis. 2016;16(1):635. infectious diseases. J Infect Dis. 2018;218:(Suppl-1):S7-11. 43. Singh N, Gayowski T, Wagener MM, et al. Clinical spectrum of 26. Patterson TF, Andriole VT. Current concepts in cryptococcosis. Eur J invasive cryptococcosis in liver transplant recipients receiving Clin Microbiol Infect Dis. 1989;8(5):457-65. tacrolimus. Clin Transplant. 1997;11(4):66-70. 27. Shourian M, Quereshi ST. Resistance and tolerance to cryptococcal 44. Odom A, Muir S, Lim E, et al. Calcineurin is required for virulence of infection: an intricate balance that controls development of Crytptococcus neoformans. EMBO J. 2007;16(10):2576-89. disease. Front. Immunol. 2019;10(66):1-11. 45. Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk 28. Meya DB, Manabe YC, Boulware DR, et al. The immunopathogenesis factors for immune reconstitution inflammatory syndrome during of cryptococcal immune reconstitution inflammatory syndrome— HAART. AIDS. 2005;19(4):399-406. understanding a conundrum. Curr Opin Infect Dis. 2016;29(1): 46. Lortholary O, Fontanet A, Memain N, et al. Incidence and risk factors 10-22. of immune reconstitution inflammatory syndrome complicating 29. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral HIV-associated cryptococcosis in France. AIDS. 2005;19(10):1043-9. therapy after diagnosis of cryptococcal meningitis. NEJM. 47. Sungkanuparph S, Filler SG, Chetchotisakd P, et al. Cryptococcal 2014;370(26):2487-98. immune reconstitution inflammatory syndrome after HAART 30. Jarvis JN, Meintjes G, Bicanic T, et al. Cerebrospinal fluid cytokine in AIDS patients with cryptococcal meningitis: a prospective profiles predict risk of early mortality and immune reconstitution multicenter study. Clin Infect Dis. 2009;49(6):931-4. inflammatory syndrome in HIV-associated cryptococcal meningitis. 48. Broom J, Woods M, Allworth A. Immune reconstitution PLoS pathogens. 2015;11(4):e1004754. inflammatory syndrome producing atypical presentations of 31. Naranbhai V, Chang CC, Durgiah R, et al. Compartmentalization of cryptococcal meningitis: case report and review of immune innate immune responses in the central nervous system during reconstitution-associated cryptococcal infections. Scand J Infect cryptococcal meningitis/HIV coinfection. AIDS. 2014;28(5):657-66. Dis. 2006;38(3):219-21. 32. Xu J, Neal LM, Ganguly A, et al. Chemokine receptor CXCR3 49. Makadzange AT, McHugh G. New approaches to the diagnosis and is required for lethal brain pathology but not pathogen treatment of cryptococcal meningitis. Semin Neurol. 2014;34(1): clearance during cryptococcal meningoencephalitis. Sci Adv. 2020;6(25):eaba2502. 47-60. 33. Hamadani BHK, Franco-Paredes C, McCollister B, et al. 50. Rajasingham R, Wake RM, Beyene T, et al. Cryptococcal meningitis Cryptococcosis and cryptococcal meningitis—new predictors diagnostics and screening in the era of point of care laboratory and clinical outcomes at a United States academic medical centre. testing. J Clin Microbiol. 2019;57(1):e01238-18. Mycoses. 2018;1(5):314-20. 51. Shibuya K, Coulson WF, Wollman JS, et al. Histopathology of 34. Warr W, Bates JH, Stone A. The spectrum of pulmonary cryptococcosis and other fungal infections in patients with cryptococcosis. Ann Intern Med. 1968;69(6):1109-16. acquired immunodeficiency syndrome. Int J Infect Dis. 2001;5(2): 35. Brizendine K, Baddley J, Pappas P. Pulmonary cryptococcosis. Semin 78-85. Respir Crit Care Med. 2011;32(6):727-34. 52. Perfect JR, Bicanic T. Cryptococcosis diagnosis and treatment: what 36. Yang M, Chang L, Sun F, et al. Comparison of cryptococcal do we know now. Fungal Genet Biol. 2015;78:49-54. meningitis in HIV-negative patients with and without lung 53. Kanjanavirojkul N, Sripa C, Puapairoj A. Cytologic diagnosis of infections.. J Int Med Res. 2020;48(6):1-9. Cryptococcus neoformans in HIV-positive patients. Acta Cytol. 37. Pastick KA, Bangdiwala AS, Abassi M, et al. Seizures in human 1997;41(2):493-6. immunodeficiency virus-associated cryptococcal meningitis: 54. Antinori S. New insights into HIV/AIDS-associated Cryptococcosis. predictors of outcome. Open Forum Infect Dis. 2019;6(11):ofz478. ISRN AIDS. 2013;2013(12):471363. 38. Chen S, Korman T, Slavin M, et al. Antifungal therapy and 55. Boulware DR, Rolfes MA, Rajasingham R, et al. Multisite validation of management of complications of cryptococcosis due to cryptococcal antigen lateral flow assay and quantification by laser Cryptococcus gattii. Clin Infect Dis. 2013;57(4):543-51. thermal contrast. Emerg Infect Dis. 2014;20(1):45-53. 39. Franco-Paredes C, Womack T, Bohlmeyer T, et al. Management 56. Skipper C, Abassi M, Boulware DR. Diagnosis and management of Cryptococcus gattii meningoencephalitis. Lancet Infect Dis. of central nervous system cryptococcal infections in HIV-infected 2015;15(3):348-55. adults. J Fungi. 2019;5(3):65.

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57. Tanner DC, Weinstein MP, Fedorciw B, et al. Comparison of 73. Tenforde MW, Shapiro AE, Rouse B, et al. Treatment for HIV- commercial kits for detection of cryptococcal antigen. J Clin associated cryptococcal meningitis. Cochrane Database Syst Rev. Microbiol. 1994;32(7):1680-4. 2018;7(7):CD005647. 58. Stamm AM, Polt SS. False-negative cryptococcal antigen test. JAMA. 74. Guidelines for the Diagnosis, Prevention and Management of 1980;244(12):1359. Cryptococcal Disease in HIV-Infected Adults, Adolescents and 59. Bloomfield N, Gordon MA, Elmendorf DF. Detection of Cryptococcus Children: Supplement to the 2016 Consolidated Guidelines on the neoformans antigen in body fluids by latex particle agglutination. Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Proc Soc Exp Biol Med. 1963;114:64-7. Geneva: World Health Organization; 2018. Available from https:// 60. Pelfrey J, Bauman S. CrAg LFA. The new gold standard for diagnosis www.who.int/hiv/pub/guidelines/cryptococcal-disease/en/ and prevention of cryptococcal disease (Cited 2015 Apr 13)(Ref.10) 75. Lawrence DS, Youssouf N, Molloy SF, et al. AMBIsome Therapy 61. Kozel TR, Bauman SK. CrAg lateral flow assay for Cryptococcosis. Induction OptimisatioN (AMBITION): High Dose AmBisome for Expert Opin Med Diagn. 2012;6(3):245-51. Cryptococcal Meningitis induction Therapy in sub-Saharan Africa: 62. Wake RM, Jarvis JN, Harrison TS, et al. Brief report: point of care Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority cryptococcal antigen screening: pipetting finger-prick blood Trial. Trials. 2018;19(1):649. improves performance of immunomycologics lateral flow assay. J 76. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management Acquir Immune Defic Syndr. 2018;78(5):574-8. of increased intracranial pressure in patients with AIDS and 63. Kenneth S, Bangdiwala A, Kwizera R, et al. Symptomatic cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS cryptococcal antigenemia presenting as early cryptococcal Cooperative Treatment Groups. Clin Infect Dis. 2000;30(1):47-54. meningitis with negative cerebral spinal fluid analysis. Clin Infect 77. Beardsley J, Hoang NLT, Kibengo FM, et al. Do intra-cerebral Dis. 2019;68(12):2094-209. cytokine responses explain the harmful effects of dexamethasone in HIV-associated cryptococcal meningitis? Clin Infect Dis. 64. Butler EK, Boulware DR, Bohjanen PR, et al. Long term 5-year 2019;68(9):1494-501. survival of persons with cryptococcal meningitis or asymptomatic 78. Eshun-Wilson I, Okwen MP, Richardson M, et al. Early versus delayed subclinical antigenemia in Uganda. PLOS One. 2012;7(12):e51291. antiretroviral treatment in HIV-positive people with cryptococcal 65. Letang E, Muller MC, Ntamatungiro AJ, et al. 2015. Cryptococcal meningitis. Cochrane Database Syst Rev. 2018;7(7):CD009012. antigenemia in immunocompromised human immunodeficiency 79. Zhai B, Wu C, Wang L, et al. The antidepressant sertraline provides virus patients in rural Tanzania: a preventable cause of early a promising therapeutic option for neurotropic cryptococcal mortality. Open Forum Infect Dis. 2015;2(2):ofv046. infections. Antimicrob Agents Chemother. 2012;56(7):3758-66. 66. Vallabhaneni S, Longley N, Smith M, et al. Implementation and 80. Rhein J, Morawski BM, Hullsiek KH, et al. Efficacy of adjunctive operational research: evaluation of a public-sector, provider- sertraline for the treatment of HIV-associated cryptococcal initiated crypto-coccal antigen screening and treatment program, meningitis: an open-label dose-ranging study. Lancet Infect Dis. Western Cape, South Africa. J Acquir Immune Defic Syndr. 2016;16(7):809-18. 2016;72(2):e37-e42. 81. Smilnak GJ, Charalambous LT, Cutshaw D, et al. Novel treatment 67. Rhein J, Bahr NC, Morawski BM, et al. Detection of high cerebrospinal of cryptococcal meningitis via neurapheresis therapy. JID. fluid levels of 1-3β-D Glucan in cryptococcal meningitis. Open 2018;218(7):1147-54. Forum Infect Dis. 2014;1(3):ofu105. 82. Rhein J, Hullsiek K, Tugume L, et al. Adjunctive sertraline in HIV- 68. Zhu J, Lin H, Wu X, et al. Metataxonomics of internal transcribed associated cryptococcal meningitis. In Conference on retroviruses spacer amplicons in cerebrospinal fluid for diagnosing and and opportunistic infections. Boston. 2018;5(8):ofy122. genotyping of cryptococcal meningitis. Chin Med J (Engl). 83. Nixon GL, McEntee L, Johnson A, et al. Repurposing and 2019;132(23):2827-34. reformulation of the antiparasitic agent flubendazole for treatment 69. Bicanic T, Wood R, Meintjes G, et al. High-dose amphotericin B with of cryptococcal meningoencephalitis, a neglected fungal disease. flucytosine for the treatment of cryptococcal meningitis in HIV- Antimicrob Agents Chemother. 2018;62(4):e01909-17. infected patients: a randomized trial. Clin Infect Dis. 2008;47(1):123-30. 84. Wiederhold NP, Najvar LK, Garvey EP, et al. The fungal Cyp51 inhibitor 70. Muzoora CK, Kabanda T, Ortu G, et al. Short course amphotericin VT-1129 is efficacious in an experimental model of cryptococcal B with high dose fluconazole for HIV-associated cryptococcal meningitis. Antimicrob Agents Chemother. 2018;62(9):e01071-18. meningitis. J Infect. 2012;64(1):76-81. 85. Oladele RO, Bongomin F, Gago S, et al. HIV-associated cryptococcal 71. Jackson AT, Nussbaum JC, Phulusa J, et al. A phase II randomized disease in resource-limited settings: a case for “prevention is better controlled trial adding oral flucytosine to high-dose fluconazole, than cure.” J Fungi. 2017;3(4):67. with short-course amphotericin B, for cryptococcal meningitis. 86. French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort AIDS. 2012;26(11):1363-70. of HIV-1 infected Ugandan adults. AIDS. 2002;16(7)1031-8. 72. Molloy SF, Kanyama C, Heyderman RS, et al. Antifungal combinations 87. McKenney J, Bauman S, Neary B, et al. Prevalence, correlates and for treatment of Cryptococcal meningitis in Africa. N Engl J Med. outcomes of cryptococcal antigen positivity among patients with 2018;378(11):1004-17. AIDS, United States, 1986–2012. Clin Infect Dis. 2015;60(6):959-65.

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88. Jarvis JN, Lawn SD, Vogt M, et al. Screening for cryptococcal 96. Rajasingham R, Boulware D. Reconsidering cryptococcal antigen antigenemia in patients accessing an antiretroviral treatment screening in the US among persons with CD4 < 100 cells/mcl. Clin program in South Africa. Clin Infect Dis. 2009;48(7):856-62. Infect Dis. 2012;55(2):1742-4. 89. Meya D, Manabe Y, Castelnuovo B, et al. Cost-effectiveness of 97. Smith KD, Achan B, Hullsiek KH, et al. Cryptococcus neoformans in serum cryptococcal antigen screening to prevent deaths among Uganda. Antimicrob. Agents Chemother. 2015;59(12):7197-204. HIV-infected persons with a CD4+ cell count of < 100 cells/μL 98. Jarvis JN, Meintjes G, Williams Z, et al. Symptomatic relapse of who start HIV therapy in resource-limited settings. Clin Infect Dis. HIV-associated cryptococcal meningitis in South Africa: the role of 2010;51(4):448-55. inadequate secondary prophylaxis. S Afr Med J. 2010;100(6):378-82. 90. Kaplan J, Vallabhaneni S, Smith R, et al. Cryptococcal antigen 99. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines screening and early antifungal treatment to prevent cryptococcal for the management of cryptococcal disease: 2010 update meningitis: a review of the literature. J Acquir Immune Defic Syndr. by the infectious diseases society of America. Clin Infect Dis. 2015;68(suppl 3):S331-9. 2010;50(3):291-322. 91. World Health Organization. Rapid advice: diagnosis, prevention 100. Tenforde MW, Lawrence DS, Wills NK, et al. Mortality from HIV- and management of Cryptococcal disease in HIV-infected adults, associated meningitis in sub-Saharan Africa- a systematic review adolescents and children. Geneva (Switzerland): World Health and meta-analysis. J Int AIDS Soc. 2020;23(1):e25416. Organization; 2011. Available from https://www.who.int/hiv/pub/ 101. Rutakingirwa MK, Cresswell FV, Kwizera R, et al. Tuberculosis in HIV- cryptococcal_disease2011/en/ associated cryptococcal meningitis is associated with an increased 92. Wake RM, Govender NP, Omar T, et al. Cryptococcal-related risk of death. J Clin Med. 2020;9(3):781. mortality despite fluconazole preemptive therapy in a cryptococcal 102. Tegume L, Rhein J, Hullsiek KH, et al. HIV-associated cryptococcal antigen screen-and-treat program. Clin Inf Dis. 2020;70(8):1683-90. meningitis occurring at relatively higher CD4 counts. JID. 93. Meya DB, Kiragga AN, Nalintya E, et al. Reflexive laboratory-based cryptococcal antigen screening and preemptive fluconazole 2019:219(6):877-83. therapy for cryptococcal antigenemia in HIV-infected individuals 103. Wykowski J, Galagan SR, Govere S, et al. Cryptococcal antigenemia with CD4 <100 cells/µL: a stepped-wedge cluster-randomised trial. is associated with meningitis or death in HIV-infected adults with J Acquir Immune Defic Syndr. 2019;80(2):182-9. VD4100 - 200 cells/mm3 BMC Infect Dis. 2020;20(1):61. 94. Sungkanuparph S, Savetamornkul C, Pattanapongpaiboon W. 104. Ramirez BC, Vega YC, Shepherd BE, et al. Outcomes of HIV-positive Primary prophylaxis for Cryptococcosis with fluconazole in human patients with cryptococcal meningitis in the Americas. Int J Inf Dis. immunodeficiency virus–infected patients with CD4 T-cell counts 2017;63:57-63. <100 cells/μL and receiving antiretroviral therapy. Clin Infect Dis. 105. Tsai W, Lee J, Hsiao W, et al. The clinical characteristics and 2017;64(7):967-70. therapeutic outcomes of cryptococcal meningitis in elderly 95. Patel S, Shin GY, Wijewardana I, et al. The prevalence of patients: a hospital-based study. BMJ Geriatrics. 2019. Available cryptococcal antigenemia in newly diagnosed HIV patients in a from https://bmcgeriatr.biomedcentral.com/articles/10.1186/ Southwest London cohort. J Infect. 2013;66(1):75-9. s12877-019-1108-0

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Enteric Fever—Challenges to 167 Overcome

Rupali Malik, Anupam Prakash

Abstract Enteric fever is an important resilient community-acquired systemic bacterial infection, commonly seen in resource limited tropical countries with overcrowding and poor sanitation, causing significant morbidity and mortality, and thus posing a grave public health challenge to reckon with. Enteric fever includes infections caused by Salmonella typhi (typhoid fever) as well as those caused by Salmonella paratyphi A, B, and C (paratyphoid fevers). Its prevention, diagnosis, as well as management pose major challenges with limited options available for empirical treatment. Thus, there is an urgent need to monitor the burden of this disease and antimicrobial resistance to guide empirical therapy and devise newer diagnostic, as well as preventive public health strategies for containment of its spread.

Introduction Although the gastric acid serves as a barrier to the entry of Salmonella through the oral route, but an excess bacterial Enteric fever is an important differential of acute load along with the lack of gastric acid in persons on undifferentiated febrile illness in developing countries. proton pump inhibitors or achlorhydria or Helicobacter It causes around 14.3 million infections annually with pylori infection, allows bacteria to traverse through the over 135,000 deaths worldwide.1 Its annual incidence stomach and reach the small intestine, where these are in our country is 493.5/100,000 persons per years with localized in the Peyer’s patches. However, once the barrier 340.1/100,000 cases per years occurring in children of 2–5 of Peyer’s patches is passed, these can reach different years, the higher incidence in children reflecting active parts of the body, and cause enteric fever and its varied 2 transmission in the community. The burden of typhoid manifestations, which can involve any organ system of the and paratyphoid fever in India as per a meta-analysis in body. Some factors which predispose to severe infection laboratory-confirmed enteric fever cases is estimated to include—primary immunodeficiencies like chronic be a prevalence of 7% for Salmonella typhi and 0.9% for granulomatous disease, neutropenia, organ transplant 2-5 Salmonella paratyphi A. recipients. Human beings are the only reservoir of this infection Incubation period can range from 6 days to 21 days and the transmission can occur either through direct (usually 2 weeks). The clinical presentation of typhoid and contact or indirectly via contact with fecal contaminated paratyphoid fever is the same except milder manifestations food or water. Sexual transmission between male partners and shorter incubation in paratyphoid fever. Most cases of has also been reported. Both genders and all age groups enteric fever are caused by the gram negative bacilli S. are infected throughout the year with a peak during the typhi; however, incidence of S. paratyphi A cases is rising summer and rainy seasons, that is, from May to October. in Asia, perhaps as a result of vaccination for S. typhi, and

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it now accounts for up to one-third of enteric fever cases in proteinuria, have also been reported rarely. Hematological India and Nepal.1,6,7 involvement can lead to bone marrow suppression, disseminated intravascular coagulation (DIC) and Clinical Features hemophagocytic lymphohistiocytosis (HLH).9 Reinfection may occur, if primary infection is Fever is the most common presenting symptom in 90%8 patients and is prolonged (>4 weeks) in untreated terminated using early intervention with antibiotics. patients. It is usually moderate to high grade and remittent nature, without touching baseline or continuous, which Differential Diagnosis rises every 3rd or 4th day, in what is classically defined Various tropical infections, like malaria, dengue, as step-ladder fashion. However, due to frequent use chikungunya, leptospirosis, and scrub typhus, are of antipyretics and antibiotics early in the course, this common differentials. However, continuous high grade pattern may not be evident always. High-grade continuous fever, coated tongue, relative bradycardia, toxic looks, fever is associated with toxemia. Non-specific abdominal and soft splenomegaly should definitely be considered a symptoms, like vomiting, diarrhea, and occasionally pointer to enteric fever. constipation, may also occur during the first week of illness. Soft splenomegaly is characteristic (to differentiate Diagnostic Challenge from the firm splenomegaly seen in malaria) and can be easily missed. Patients with enteric fever usually Diagnosis of enteric fever poses an immense challenge as have a coated tongue and relative bradycardia. Patient blood culture, which is considered the gold standard, has 11 can also have jaundice because of liver involvement a low sensitivity of 40–60%. Moreover, in our country, (enteric hepatitis), breathlessness, and wheezing (enteric delayed presentations with pre-exposure to inadequate bronchitis), obtundation, delirium and coma (enteric and unnecessary antibiotic therapy prior to visiting a encephalopathy), bone marrow depression, cholecystitis, proper health-care facility hinders its performance. loose motions, that is, classically pea-soup diarrhea Though it is positive in the first week itself and also provides (enteritis), intestinal perforation, and skin rash (Rose sensitivity testing for antibiotics, it takes longer time, thus spots—2–5 mm diameter macular lesions seen transiently delaying treatment. Newer commercially available rapid ® during the second week of illness, considered to be due to serological tests, like TUBEX TF (IDL, Sweden) and ® bacterial emboli). Serious complications usually occur in Typhidot (Malaysian Biodiagnostic Research, Malaysia), the second week of illness. Intestinal perforation occurs in can also be used as point of care tests in an emergency about 1–3% of hospitalized patients with enteric fever, with setting for early diagnosis. The former is an antibody- common site being terminal ileum (70–80%) followed by based test based on the principle of inhibition reaction less commonly involved sites like jejunum, ceacum, colon, between host and in vitro antibodies that compete for or gall bladder. Gall bladder may remain a preserved focus S. typhi specific lipopolysaccharide, while latter is a in partially treated patients of enteric fever, and lead to qualitative enzyme-linked immunosorbent assay (ELISA) a carrier state, wherein the patient may keep shedding based test that detects immunoglobulin G (IgG) and bacteria in stools for months or years, becoming a public immunoglobulin M (IgM) antibodies against S. typhi outer health hazard. The prolonged asymptomatic carrier state membrane protein. They have sensitivity of 55–70% and can be seen in about 10–15% of patients.9 specificity of more than 85%.12 These kits perform better Atypical manifestations of enteric fever have also among hospitalized patients than those evaluated in the been reported including ataxia, sensorineural deafness, community setting. Serum Widal test provides the titers of meningism, Guillain-Barré syndrome (GBS), myocarditis, antibodies to somatic ‘O’ and flagellar ‘H’ antigens, and is acute respiratory distress syndrome (ARDS), osteomyelitis, helpful in the second week of fever onwards. A titer more etc. Complications, like osteomyelitis, mycotic aneurysms, than or equal to 1:160 is considered positive in endemic and soft tissue abscesses, are reported more often in areas as in India, although rising titers in paired sera can paratyphoid infections.10 Renal complications, like be very helpful. Third week stool culture and fourth week glomerulonephritis, pyelonephritis, cystitis, and mild urine culture may be helpful; however, untreated patients

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are more likely to develop complications in the third and Oral azithromycin 20 mg/kg once daily (to a maximum fourth week of fever. In partially treated patients, blood of 1 g daily) for 7 days has been recommended for treatment culture may not be positive, but bone marrow culture may of uncomplicated enteric fever, and is considered to be still be positive. Directed investigations may be dictated by equiefficacious to intravenous ceftriaxone (75 mg/kg/day to the suspicion of various complications. Thus, the existing maximum 2.5 g/day) given for 7 days, with less chances of diagnostic tests suffer from limitations regarding time relapse and similar adverse effect profile.15 A 5-day course cycle, sensitivity, infrastructure need, etc, emphasizing the of azithromycin has also been reported to be efficacious.16 need for newer, more accurate, and rapid point-of-care In a study from Delhi, India,15 resistance to co- diagnostic tests. trimoxazole, chloramphenicol, ceftriaxone, and azithro- Complete blood counts usually suggest leukocytosis, mycin were reported to be 6.1%, 13.8%, 16.1%, and 5.78%, but bone marrow suppression can be associated with respectively over a 7-year period. Multidrug-resistant S. normocytic normochromic anemia, leukopenia, and typhi and S. paratyphi A were reported to be 2.73% and thrombocytopenia. Transaminitis with mild elevation of 1.91%, respectively. In a recent systematic review and serum bilirubin levels may be observed. Kidney functions meta-analysis, multidrug-resistant S. typhi was reported to are normal, but insensible losses due to high fever and be 9% and multidrug-resistant S. paratyphi as 2% in South anorexia because of toxemia can result in prerenal Asia. Besides, fluoroquinolone non-susceptible S. typhi azotemia. and S. paratyphi were pegged at 70% and 53%, respectively in South Asia.17 Resistance rates for various agents are Management Challenge highly variable from study to study and region to region, but resistance rates to azithromycin appear lowest among Mainstay for management of enteric fever is to give all the antibiotics. antibiotics along with use of antipyretics and maintenance There is a decrease in culture positive cases these days, of hydration and adequate nutrition. Conventionally, which may suggest a decrease in the burden of disease, chloramphenicol 1–2 g IV 8-hourly used to be the gold but can also be a reflection of the early empirical antibiotic standard of treatment; however, with advent of newer use to treat typhoid fever in the community. There is a potent antibiotics in the 1990s and due to idiosyncratic possibility that due to the emerging antibiotic resistant complication of chloramphenicol, like aplastic anemia, strains, under the selective pressure of antibiotic use, its use was abandoned. Cotrimoxazole and ampicillin only patients who fail to respond to empirical therapy were other agents used. Use of aminoglycosides was visit tertiary care hospitals. Thus, culture positive cases precluded as they were injectable drugs with well- may represent only a small proportion of total number known neurotoxicity, nephrotoxicity, and ototoxicity. of cases in a community and this may lead to skewing of Multidrug-resistant (MDR) strains resistant to ampicillin, antimicrobial susceptibility data toward resistance. trimethoprim-sulfamethoxazole, and chloramphenicol, Some treating physicians prefer to use two agents soon became prevalent worldwide, though they are simultaneously to treat enteric fever. But this seems now decreasing with wider use of other antibiotics, but justifiable only in patients who have enteric fever development of increasing resistance to fluoroquinolones with complications and in patients having no clinical as well as even cephalosporins is a growing challenge now. improvement with monotherapy. It may be prudent to Quinolones are an effective group, and ciprofloxacin, start with a single agent in uncomplicated enteric fever, ofloxacin, lomefloxacin, and levofloxacin were all and once susceptibility report is obtained decision on rampantly used with great effect. But due to rising adding a second agent or switching to another agent fluoroquinolones resistance, ciprofloxacin is no longer the can be taken. Role of various fixed drug combinations empirical choice of treatment in our country.13 available still needs further evaluation. Ceftriaxone and cefixime are currently considered the treatment of choice, but there are also reports on increased minimum inhibitory concentration (MIC) to ceftriaxone Prevention and Control Challenge causing delayed defervescence and even reports on the Three vaccines are commercially available for typhoid full resistance.14 fever, one live attenuated oral vaccine and two injectable

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inactivated vaccines, with limited efficacy (50–72%). . 2 John J, Van Aart CJC, Grassly NC. The burden of typhoid and , is an oral live attenuated S. typhi vaccine (given on paratyphoid in India: systematic review and meta-analysis. PLoS days 1, 3, 5, and 7, with a booster every 5 years). It is not Negl Trop Dis. 2016;10:e0004616. . 3 Crump JA, Sjölund-Karlsson M, Gordon MA, et al. Epidemiology, given in children less than 6 years. Vi CPS is a parenteral clinical presentation, laboratory diagnosis, antimicrobial resistance, vaccine consisting of purified Vi polysaccharide from and antimicrobial management of invasive Salmonella infections. the bacterial capsule (given in one dose, with a booster Clin Microbiol Rev. 2015;28:901-37. every 2 years). It is not given in children less than 2 years. . 4 Arndt MB, Mosites EM, Tian M, et al. Estimating the burden of Third, is an injectable typhoid (TCV), paratyphoid a in Asia and Africa. PLoS Negl Trop Dis. 2014;8:e2925. . 5 Dahiya S, Malik R, Sharma P, et al. Current antibiotic use in consisting of Vi polysaccharide antigen linked to tetanus the treatment of enteric fever in children. Indian J Med Res. toxoid protein. It can be used in children from 6 months 2019;149(2):263-9. of age and adults up to 45 years of age. No vaccine for . 6 Maskey AP, Day JN, Phung QT, et al. Salmonella enterica serovar paratyphoid fever is presently available.12 Paratyphi A and S. enterica serovar Typhi cause indistinguishable Public health measures like availability of safe food clinical syndromes in Kathmandu, Nepal. Clin Infect Dis. and water, adequate sanitation services, and proper 2006;42(9):1247-53. doi: 10.1086/503033. 7. Ochiai RL, Wang X, von Seidlein L, et al. Salmonella paratyphi A rates. personal hygiene (WASH) are important to prevent 12 Asia Emerg Infect Dis. 2005;11(11):1764-6. enteric fever. The challenge of controlling typhoid fever 8. Kumar P, Kumar R. Enteric fever. Indian J Pediatr. 2017;84:227-30. is often compounded by the lack of adequate nationwide 9. Ismail J, Singhi S. Enteric fever. J Pediatr Crit Care. 2017:4(3):79-84. surveillance in the affected countries. Recently in India, 10. Bhan M, Bahl R, Bhatnagar S. Typhoid and paratyphoid fever. The a study titled “National Surveillance System for Enteric Lancet. 2005;366:749-62. Fever in India (NSSEFI)” is being done to estimate the 11. Thriemer K, Ley B, Menten J. A systematic review and meta-analysis of the performance of two point of care typhoid fever tests, Tubex incidence of typhoid fever in age-specific manner in TF and Typhidot, in endemic countries. PloS One. 2013;8:e81263. 18 children between 6 months and 15 years. 12. Mukhopadhyay B, Sur D, Gupta SS, et al. Typhoid fever: control & challenges in India. Indian J Med Res. 2019;150(5):437-47. Conclusion 13. Renuka K, Kapil A, Kabra SK, et al. Reduced susceptibility to ciprofloxacin and gyra gene mutation in North Indian strains of In this era of emerging antibiotic resistant strains, with no new Salmonella enteric serotype typhi and serotype paratyphi A. Microb drug in the horizon, there is an imperative need for continuous Drug Resist. 2004;10:146-53. surveillance to inform clinicians regarding early diagnosis 14. Sharma P, Dahiya S, Manral N, et al. Changing trends of culture- and better management of infections with use of effective positive typhoid fever and antimicrobial susceptibility in a tertiary antibiotic policies and also government policymakers for care North Indian hospital over the last decade. Indian J Med strengthening preventive strategies like adequate sanitation Microbiol. 2018;36:70-6. with safe food and water supply, along with development of 15. Nair BT, Simalti AK, Sharma S. Study comparing ceftriaxone with azithromycin for the treatment of uncomplicated typhoid fever in new vaccines that are effective against both S. typhi as well as children in India. Ann Trop Med Public Health. 2017;10:205-10. S. paratyphi A infections. Though challenges persist in all these 16. Frenck RW, Mansour A, Naik I, et al. Short-course azithromycin for aspects hindering implementation of facilities available, an the treatment of uncomplicated typhoid fever in children and integrated approach with a comprehensive policy framework adolescents. Clin Infect Dis. 2004;38:951-7. is required for prevention, control, and elimination of enteric 17. Makkar A, Gupta S, Khan ID, et al. Epidemiological profile and fever. antimicrobial resistance pattern of enteric fever in a tertiary care hospital of north India—a seven year ambispective study. Acta Medica. 2018;61:125-30. References 18. John J, Bavdekar A, Rongsen-Chandola T, et al. Estimating the . 1 Browne AJ, Hamadani BHK, Kumaran EAP, et al. Drug-resistant incidence of enteric fever in children in India: a multi-site, active enteric fever worldwide, 1990 to 2018: a systematic review and fever surveillance of pediatric cohorts. BMC Public Health. meta-analysis. BMC Med. 2020;18:1-22. 2018;18(1):594.

MU-167.indd 1099 29-01-2021 15:13:00 CHAPTER Leptospirosis and Brucellosis— Can These Be Difficult to 168 Diagnose?

Saurabh Srivastava, Amit Gupta, Indal Chauhan

Abstract Zoonotic diseases are important for humans as they may cause disease in them and are recognized as important public health issue. Brucellosis and leptospirosis are important zoonotic diseases of public health importance. The clinical presentation of these disorders mimics many other common diseases. The present chapter summarizes the important manifestation of these disorders and there differentiating aspects with other diseases.

Introduction Relapses can occur after primary infection and disease can also be chronic. Zoonoses are diseases transmitted from animals to man have been recognized as important public health issues for centuries. Brucellosis and leptospirosis are Pathogenesis and Modes of Transmission important infections in animal handlers causing wide Human transmission in brucellosis occurs through direct range of similar clinical manifestation. Butchers and contact with infected animal, ingestion of unpasteurized slaughterhouse workers are at high risk of contracting milk and milk products, or carcasses of infected animal. zoonotic diseases due to handling of animals or by Human brucellosis is usually associated with ingestion of unpasteurized milk or milk products. Non- domestic or occupational exposure to infected animals specific symptoms including fever lead to chronic disease or their products. Veterinarians, shepherds, farmers, due to misdiagnosis. Zoonoses should be suspected if goatherds, and employees of meat-processing plants and there are infection’s protean manifestations along with slaughterhouses in endemic areas are occupationally appropriate exposure history. Hence, in this chapter, we exposed to infection. Laboratory workers who handle seek to summarize brucellosis and leptospirosis infection cultures or infected samples are also at risk. Travelers in human. and urban residents usually acquire the infection through consumption of contaminated foods. The most frequently Brucellosis implicated sources of infection are dairy products, Livestock animals are mainly affected by brucellosis. It is especially soft cheeses, unpasteurized milk, and ice caused by the small, Gram-negative coccobacilli of the cream, under exceptional circumstances raw meat and genus Brucella. Main species causing disease in humans bone marrow can also be source of infection. Infections are Brucella melitensis (sheep and goat), Brucella suis acquired through cosmetic treatments using materials (pigs), and Brucella abortus (cattle). The disease has of fetal origin have been reported. Person-to-person worldwide distribution and is mainly seen in rural areas. transmission is extremely rare, as is transfer of infection

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by blood or tissue donation. No evidence of increased „„ Pulmonary complications: Respiratory symptoms are severity and prevalence of Brucellosis in immunodeficient reported by 15–25% of patients but radiological changes individuals and persons infected with human immuno­ are seen in less than 10%.5 They range from flu-like deficiency virus, even though it is a chronic intracellular symptoms to bronchitis, lobar pneumonia, interstitial infection.1 pneumonitis, lung abscesses, hilar lymphadenopathy, and lung effusions. Clinical Features „„ Genitourinary complications: Complications from The severity of brucellosis is related to infecting species, the genitourinary tract are rare. Acute orchitis or biotype, and host factors. B. melitensis and B. suis can cause epididymo-orchitis with signs of systemic infection severe disease in humans, with B. abortus usually being can occur in males and there can be pyelonephritis associated with milder disease. Human infection with B. resembling tuberculosis, particularly in females. canis is rare. Human brucellosis can be associated with „„ Neurologic complications: Depression is a common acute, sub-acute, relapsing, and chronic manifestations. complaint, but invasion of the central nervous system The incubation period is normally between 2 and 4 weeks, occurs in only 2–4% of cases. It usually presents as acute but it may be months. or chronic meningitis. Encephalitis, polyradiculopathy, Acute brucellosis can present as a non-specific psychosis, and meningovascular complications febrile illness characterized by intermittent or remittent have also been described, as well as rarer complex fever (39–40°C). The fever may be associated with chills, abscesses.6 night sweats, joint and muscle pain, weight loss, fatigue, „„ Cardiovascular complications: Endocarditis, although malaise, headache, and adenopathy mainly in children. rare, is the main cause of death related to brucellosis.1,4 It may also be associated with non-specific The aortic valve is more often involved than the gastrointestinal disorders, hepatomegaly and/or mitral valve. Other complications include mycotic 2 splenomegaly, cough, arthritis (knee), and orchitis. aneurysms, myocarditis and pericarditis. Waxing and waning type of fever is characteristic of „„ Cutaneous involvement: Cutaneous manifestations sub-acute brucellosis and is also known as undulant fever. of brucellosis consist mainly of transient nonspecific It is often low grade, persists for weeks, accompanied lesions including erythema nodosum, petechiae, by arthralgia, arthropathy and diminished well- vasculitis, papules, and rashes. being. Undulant fever is more common in adults than in children and can involve specific organ systems. Diagnosis Intrauterine infection, miscarriage, premature delivery, and spontaneous abortion are common during infection The diagnosis should be considered in a case of chronic of human brucellosis in pregnancy.3 febrile illness having epidemiological risk factors along with osteoarticular involvement (axial spine or sacroiliac Localized Form joints), uveitis or other focal lesions described earlier. Primary infection may progress to localized infection Confirmatory diagnosis is usually based on microbiologic 7 (even several months or years later): culture of blood, tissues, or bone marrow. Blood culture, „„ Osteoarticular: Sacroiliac joint, lower limbs joints, which is gold standard for diagnosis, is positive only in the 2 spine (vertebral osteomyelitis, intervertebral disk acute phase and has sensitivity of less than 50–70%. Bone infection) marrow cultures are more sensitive than blood cultures in „„ Genitourinary: Orchitis, epididymitis acute brucellosis and remain positive even in later course 8,9 „„ Pulmonary: Bronchitis, pneumonia, pleurisy of the infection, along with antimicrobial treatment. „„ Neurological: Meningitis, encephalitis, polyneuritis Body fluids, such as cerebrospinal fluid (CSF) or joint fluid, show lymphocytosis, low glucose levels and Complications of Brucellosis high protein concentration. Elevated CSF adenosine „„ Osteoarticular complications: Affect 20–40% of patients. deaminase levels are also present. Biopsied samples Sacroiliitis is the most common reported complication, of tissues such as lymph node or liver may show especially when B. melitensis predominates.1,4 noncaseating granulomas without acid/alcohol-fast

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bacilli. In recent years, matrix-assisted laser desorption High relapse rates reported with monotherapeutic ionization time-of-flight spectrometry (MALDI-TOF MS) approaches so multidrug antimicrobial regimens are has emerged as a powerful tool in bacterial identification. the mainstay of therapy. The risk of relapse is not well The peripheral blood-based polymerase chain reaction understood and resistance is not a significant issue in detects bacteremia, to predict relapse, and to exclude treatment of brucellosis.11 “chronic brucellosis.”10 Same treatment is to be given for localized forms of Serologic tests are more sensitive than culture. the infection, but for a period of 6 weeks to 4 months The serum agglutination test (SAT) remains the best depending on the focus. standardized and most widely used serologic test.8 Other serological tests are indirect immunofluorescence, Wright Leptospirosis agglutination test, Rose Bengal, ELISA, etc. and provide Leptospirosis is an important zoonotic disease globally presumptive diagnoses. caused by spirochetes of the genus Leptospira. Malaria and tuberculosis are to be ruled out in endemic Leptospirosis affects almost all domestic and wild animals regions. worldwide except Antarctica. Rodents (rat), dogs, and cattle are mainly affected. It is a disease of public health Radiography importance in tropics and is seen in agricultural workers14 Small erosions or destruction or joint space narrowing is as well as urban slum residents.15 Disease is endemic seen in ankles, knees, hips, vertebrae, and sacroiliac joint. throughout the world; however, outbreaks superimposed Chest radiograph is often normal but sometimes pleural on endemic disease activity are regularly linked to severe effusion can be present. hurricane and flooding events.

Management (Table 1) Pathogenesis and Modes of Transmission The goal of medical therapy is to control symptoms Human transmission of leptospirosis occurs by contact quickly, in order to prevent complications and relapses. of moist soil or freshwater contaminated with urine of

TABLE 1 Management of brucellosis

Children under 8 years12 Rifampicin + Co-trimoxazole or Gentamicin + Co-trimoxazole Children 8 years and over Rifampicin + Doxycycline or Gentamicin + Doxycycline Adults13 Rifampicin + Doxycycline or Doxycycline + Streptomycin or Gentamicin Pregnant/breastfeeding women Rifampicin occasionally Rifampicin + co-trimoxazole Sacroiliitis Doxycycline + Rifampin + Gentamicin—2–3 weeks Then Doxycycline + Rifampicin for 6 weeks Nervous system infection Doxycycline + Streptomycin + Rifampicin or Doxycycline + Co-trimoxazole + Rifampicin Co-trimoxazole: PO for 6 weeks Children < 8 years: 20 mg SMX + 4 mg TMP/kg 2 times daily Doxycycline: PO for 6 weeks Children ≥ 8 years: 1–2 mg/kg 2 times daily Adults: 100 mg 2 times daily Rifampicin: PO for 6 weeks Children: 15–20 mg/kg once daily (max. 600 mg daily) Adults: 600–900 mg once daily Gentamicin: IM for 2 weeks Children and adults: 5 mg/kg once daily Streptomycin: IM for 2 weeks Adults: 1 g once daily

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an infected animal (indirect contact) or direct contact of „„ May be associated with: blood, urine, and other body fluids or tissues of an infected „„ Gastrointestinal symptoms (abdominal pain, nausea, animal through skin lesions or mucous membranes. anorexia, vomiting) Leptospires are shed in urine as they colonize proximal „„ Non-productive cough renal tubules of mammalian hosts. They can survive „„ Adenopathies for several months in the environment under moist „„ Hepatomegaly conditions; factors affecting survival are the presence of Immune phase: warmth (above 22°C) and neutral pH (pH 6.2–8.0). Rodents „„ The signs of the acute phase regress after 5–7 days then are a particularly important reservoir. Some serovars reappear for a few days but are usually mild (milder appear to be preferentially adapted to select mammalian fever, less severe myalgia) and then disappear. hosts; examples are the serovar Icterohaemorrhagiae „„ Coincide with the appearance of antibodies, and which is primarily associated with the Norway rat, leptospires can be cultured from the urine. pomona with swine and cattle and canicola with dogs. „„ Aseptic meningitis is the hallmark of immune phase However, a particular host species may serve as a reservoir of leptospirosis but is not associated with mortality. for one or more serovars, and a particular serovar may Cerebrospinal fluid pleocytosis can be demonstrated colonize different animal species. Transmission of in 80–90% of patients during the second week of infection in humans usually occurs through contact illness. Clinical signs and symptoms of meningitis are with contaminated water or moist soil. Organisms enter seen in only 50% cases. humans through the mucosal surface of the nasopharynx, „„ Uveitis is a late manifestation of leptospirosis. It mouth, eye, or esophagus or through abrasions of the is generally seen after 4–8 months of illness. Most skin. Risks of leptospirosis transmission and exacerbation frequently affected area is anterior uveal tract. are increased due to migration of the rural poor to Common symptoms of uveitis are photophobia, pain, urban slums. Intense exposure to leptospires has been and blurring of vision. documented in workers of sugarcane, rice, and rubber plantation. Leptospirosis is also acquired by direct contact with the urine, blood, or tissues of infected animals but is Severe or Ictero-hemorrhagic Form less frequent. (Weil’s Disease) The onset is the same but a few days later the symptoms Clinical Features worsen: Severe, icteric illness occurs in less than 10% of „„ Renal disorders (oliguria or polyuria or anuria) symptomatic infections; however, subclinical infection is „„ Hepatic disorder (jaundice—appears 5–9 day of illness, very common. Majority of cases of leptospirosis are mild, hepatomegaly) presenting as febrile illness, but disease can be potentially „„ Widespread hemorrhages (ecchymoses, haemoptysis, fatal leading to multiorgan dysfunction. The incubation purpura, epistaxis, etc.) period is usually 1–2 weeks but ranges from 1 to 30 days.16 „„ Pulmonary signs (chest pain) Leptospirosis is classically described as biphasic. „„ Cardiac signs (myocarditis, pericarditis) Acute phase (leptospiremic/septic/anicteric phase): „„ Refractory shock characterized by: „„ Death occur from subarachnoid hemorrhage or „„ High fever with chills of sudden onset (3–10 days gastrointestinal bleeding duration) „„ Eye signs: Conjunctival hemorrhage, scleral icterus, „„ Headache and conjunctival suffusion „„ Muscle pain (especially calf pain) „„ Leptospirosis-associated severe Pulmonary „„ Photophobia Hemorrhage Syndrome is as a widespread public „„ Ocular pain health problem having a case fatality rate of about 50% „„ Bilateral conjunctival hemorrhage is very frequent „„ Apparent critical threshold for severe outcomes such „„ Organism can be cultured from blood and detected by as SPHS and death is leptospiremia of 10,000 or more polymerase chain reaction bacteria per milliliter of blood

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Diagnosis Modified World Health Organization (WHO) criteria TABLE 2 Leptospirosis may be difficult to distinguish from other for diagnosis of leptospirosis infectious causes of fever, and a high index of suspicion Part A: Clinical data is required based on the local epidemiology. Modified Headache 2 Points World Health Organization (WHO) Faine’s criteria (with Fever 2 Points amendment) 2012 Criteria for Diagnosis of Leptospirosis Temperature >39*C 2 Points is summarized in Table 2.17 Conjunctival suffusion 4 Points Laboratory diagnosis is difficult to obtain. The routine Myalgias 4 Points investigation demonstrates: Meningeal signs 4 Points „„ Complete blood count: Anemia, polymorphonuclear Conjunctival suffusion + meningism + myalgia 10 Points leukocytosis, or thrombocytopenia. Jaundice 1 Points „„ Urine: Leukocyturia, proteinuria, possible microscopic Albuminuria /Nitrogen retention 2 Points hematuria. Haemoptysis / Dyspnea 2 Points „„ Enzyme markers of skeletal muscle damage are elevated in the sera of 50% of patients during the first Part B: Epidemiological factors week of illness, such as creatine kinase, aldolase, etc. Heavy rainfall 5 Points Contact with contaminated environment 4 Points „„ Hyperbilirubinemia, prolongations of the prothrombin time, and modest elevations of serum alkaline Animal contact 1 Points phosphatase are typical. There is mild hepatocellular Part C: Bacteriological and laboratory Findings necrosis in Weil’s disease. Isolation of leptospira in culture Diagnosis certain „„ Elevated markers of inflammation (C-reactive PCR 25 Points protein level, procalcitonin level, and erythrocyte Positive IgM ELISA 15 Points sedimentation rate). Slide Agglutination test (SAT) Positive 15 Points MAT single high titer 15 Points Serology MAT Rising titer/seroconversion (Paired sera) 25 Points Presumptive leptospirosis if score „„ Between 0 and 7 days: Real-time PCR (early diagnosis) zz Part A or Part A & Part B score: 26 or more „„ After 7 days: Microscopic agglutination test (MAT); IgM zz Part A, B, C (Total): 25 or more ELISA test provides presumptive diagnosis Possible leptospirosis if score between 20-25 points „„ After 10 days: MAT and IgM ELISA tests only. ELISA—enzyme linked immunosorbent assay —— Culture: Limited use (bacteria grow slowly, specific IgM—Immunoglobin M culture medium) MAT—Microscopic agglutination test

Radiography TABLE 3 Management of leptospirosis The most common radiographic finding is a bilateral patchy alveolar pattern that corresponds to scattered Indication Regimen alveolar hemorrhage. These abnormalities predominantly Mild leptospirosis zz Doxycycline 100 mg twice a day or zz Amoxycillin 500 mg thrice a day or affect the lower lobes. Other findings include pleura-based zz Ampicillin 500 mg thrice a day densities (representing areas of hemorrhage) and diffuse Moderate/Severe zz Penicillin 1.5 million units IV or IM 6 hourly or ground-glass attenuation typical of acute respiratory leptospirosis zz Ceftriaxone 2 gm/day IV or distress syndrome (ARDS). zz Cefotaxime 1 gm IV 6 hourly zz Doxycycline 200 mg IV loading followed by Management (Table 3) 100 mg IV 12 hourly Chemoprophylaxis zz Doxycycline 200 mg PO once a week or Management should be started on high index of suspicion zz Azithromycin 250 mg PO once or twice a as early intervention may prevent the development of week multiorgan failure and antibiotics are less likely to benefit All regimens to be given for 7 days. Aggressive supportive care in once organ damage has occurred.10 leptospirosis essential and can be lifesaving.

MU-168.indd 1104 29-01-2021 15:08:07 Leptospirosis and Brucellosis—Can These Be Difficult to Diagnose? CHAPTER 168 1105 Chest radiograph No changes Soft miliary mottling, nodules, Parenchymal hilar consolidation, or paratracheal lymphadenopathy, pneumothorax Consolidation Infiltrates effusion Pleural Military shadows Mostly normal Multiple ill - defined nodules in both lungs Consolidation Infiltrates Normal Bi-basal air space Bi-basal air space perihilar opacities, and alveolar reticular infiltrates Bronchial wall thickening, thickening, wall Bronchial nodules, Centrilobular glass attenuation, Ground consolidation Usually normal Usually Sometimes pleural effusion Physical and laboratory Physical findings Hepatosplenomegaly Hepatosplenomegaly, Hepatosplenomegaly, painful lymphadenopathy Hepatosplenomegaly effusion Pleural lymphadenopathy Renal and hepatic dysfunction Splenomegaly lymphadenopathy Hepatomegaly Icterus Hemoptysis suffusion Conjunctival Renal and hepatic dysfunction Hepatosplenomegaly Hepatosplenomegaly Icterus – Abnormal LFT Hepatosplenomegaly effusion Pleural lymphadenopathy – _ – – + + + + + +/– Diarrhea abdominal tuberculosis – – + + ++ ++ +/– +/– +/– +/– Confusion – + + + + + + + ++ ++ Myalgia – + + + + ++ +/– +/– +/– +/– pain Joint – + +/– Sore throat – – – – +/– – – Symptoms – – – – + rash Rash lesions Blanching ++ purpuric part of body Hemorrhagic rash over legs over rash erythematous maculopapular Eschar for lower lower for Eschar – – + + ++ ++ ++ +/– +/– +/– Dyspnea - – – + + ++ +/– +/– +++ +++ Headache – – – – + + + ++ ++ +/– Sputum – – – + + ++ ++ ++ ++ ++ Cough Cough + + + ++ ++ ++ ++ ++ ++ rise fever fever Fever biphasic + evening + evening continuous continuous Differentiating clinical features of various diseases of various Differentiating clinical features TABLE 4 TABLE Disease Brucellosis Tuberculosis Leptospirosis Legionellosis Malaria Rickettsial Disease (Scrub Typhus) Influenza Mycoplasma Mycoplasma pneumonia Dengue Enteric fever Enteric

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Differentiating Brucellosis and 4. Dean AS, Crump L, Greter H, et al. Clinical manifestations of human brucellosis: a systematic review and meta-analysis. PLoS Negl Trop Leptospirosis with Other Diseases Dis. 2012;6(12):1929. The differential diagnosis of these infections is broad, 5. Erdem H, Inan A, Elaldi N, et al. Respiratory system involvement in brucellosis: the results of the Kardelen study. Chest. 2014;145(1): reflecting the diverse clinical presentations of the disease. 87-94. When fever, headache, and myalgia predominate, . 6 Erdem H, Kilic S, Sener B, et al. Diagnosis of chronic brucellar influenza, and other common and less common viral meningitis and meningoencephalitis: the results of the Istanbul-2 infections (e.g., dengue and chikungunya) should be study. Clin Microbiol Infect. 2013;19(2):80-6. considered. Malaria, typhoid fever, Rickettsial diseases . 7 Young EJ. Brucellosis: current epidemiology, diagnosis, and management. Curr Clin Top Infect Dis. 1995;15:115-28. may mimic the early stages of disease and are important . 8 Al Dahouk S, Nöckler K. Implications of laboratory diagnosis on to recognize. Dual infections have been reported. In this brucellosis therapy. Expert Rev Anti Infect Ther. 2011;9(7):833-45. light, it is advisable to conduct testing for other diseases . 9 Gotuzzo E, Carrillo C, Guerra J, et al. An evaluation of diagnostic also. Some common features to differentiate these methods for brucellosis—the value of bone marrow culture. J infections with other common infections are shown in Infect Dis. 1986;153(1):122-5. 10. Beeching NJ, Carbel MJ. Brucellosis. In: Kasper F (Ed). Harrison’s Table 4. Principles of Internal Medicine, 19th edition. United States of America: McGraw Hill Education; 2015. p. 1066. Conclusion 11. Maves RC, Castillo R, Guillen A, et al. Antimicrobial susceptibility of Brucella melitensis isolates in Peru. Antimicrob Agents Chemother. Brucellosis and leptospirosis have diverse clinical presentations, 2011;55(3):1279-81. so these diseases have to be differentiated from many common 12. Yousefi-Nooraie R, Mortaz-Hejri S, Mehrani M, et al. Antibiotics disorders like influenza, malaria, dengue, typhoid, and for treating human brucellosis. Cochrane Database Syst Rev. rickettsial diseases. Although, management of these diseases is 2012;10(10):007179. not difficult but early diagnosis is key to better outcome. 13. Lubani MM, Dudin KI, Sharda DC, et al. A multicentre therapeutic study of 1100 children with brucellosis. Pediatr Infect Dis J. 1989;8(2):75-8. 14. Bharti AR, Nally JE, Ricaldi JN, et al. Leptospirosis: a zoonotic disease References of global importance. Lancet Infect Dis. 2003;3(12):757-71. 1. Franco MP, Mulder M, Gilman RH, et al. Human brucellosis. Lancet 15. Ko AI, Galvao Reis M, Dourado CMR, et al. Urban epidemic of severe Infect Dis. 2007;7(12):775-86. leptospirosis in Brazil. Lancet. 1999;354(9181):820-5. . 2 Pappas G, Akritidis N, Bosilkovski M. Brucellosis. N Engl J Med. 16. Haake DA, Levett PN. Leptospirosis in humans. Curr Top Microbiol 2005;352:2325-36. Immunol. 2015;387:65-97. . 3 Arenas-Gamboa AM, Rossetti CA, Chaki SP, et al. Human 17. Sethi S, Sharma N, Kakkar N, et al. Increasing trends of leptospirosis brucellosis and adverse pregnancy outcomes. Curr Trop Med Rep. in Northern India: a Clinico-Epidemiological Study. PLOS Neglected 2016;3(4):164-72. Tropical Diseases. 2010;4(1):579.

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Growing Threat of Klebsiella— 169 How to Counter?

Aditya Prakash Misra

Abstract Klebsiella pneumoniae is an important pathogen that belongs to family Enterobacteriaceae. Incidence of extended spectrum beta lactamases (ESBL) producing Gram-negative bacteria has gradually increased in last 2–3 decades. Problem is further compounded by carbapenemase producing Gram-negative bacteria. Carbapenem-resistant Enterobacteriaceae (CRE) has become a global threat recently. WHO in a policy statement in 2017 had mentioned that future development of antimicrobial agents should focus on CRE.1 Klebsiella is the most important pathogen of CRE family encountered all over the world.

Introduction resistant Klebsiella pneumoniae exceeds 60% despite the combination therapy.4 Edwin Klebb in 1875 had described Klebsiella, Klebsiella pneumoniae is the main pathogenic as a Gram-negative bacterium belonging to family organism in the genus. In some cases K oxytoca have been Enterobacteriaceae. Klebsiella is part of microbiome in isolated from human clinical specimens. Klebsiella can be healthy individuals and colonizes mainly gastrointestinal differentiated into various types by biotyping, serotyping, system. It can cause severe infections in critically ill and phage typing, bacteriocin typing and molecular typing. immune-compromised patients. Klebsiella causes urinary Serotyping is most commonly used and is based on tract infection, pneumonias, blood stream infections, capsule antigens. liver abscesses, necrotizing fasciitis, meningitis and surgical site infections, mainly. Kaur et al. from a single tertiary care center in Delhi reported 69.3% mortality in Pathogenicity patients suffering from colistin-resistant K pneumonia Pathogenicity of Klebsiella depends upon these factors— infections.2 Another study from South India reported Capsular antigens: Klebsiella has a capsule made of high rates of resistance to Carbapenem, Minocycline, complex acidic polysaccharides. Capsular antigens are and Tigecycline in isolates of Klebsiella blood stream essential to virulence and have been divided into 79 infections.3 Carbapenem resistance had increased serotypes. Klebsiella strains of K1, K2, K4, and K5 are more during the study period. High resistance of Klebsiella to virulent. various antibiotics is also reported from China, Korea, Greece, other European countries, and the USA. Falagas Fimbriae: Fimbriae (Pili) are filamentous projections on et al. have shown that mortality due to carbapenem- bacterial surface by which it attaches to the host surface.

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Fimbriae help in developing biofilms and also help assays though expensive, but help clinicians in de- organism to adhere to medical devices. escalation of therapy, avoiding unnecessary antibiotics, reducing length of stay and mortality.9 Lipopolysaccharide: Helps in evading host’s defense mechanisms. Mechanisms for Antibiotic Resistance Siderophores: Iron is an essential factor in bacterial As early as 1970s, aminoglycoside resistant Klebsiella were growth. The level of free bioavailable iron is too low for noted. Since 1982, strains that produce ESBL, making bacteria growth. Klebsiella secretes high affinity, low them resistant to extended spectrum cephalosporins molecular weight iron chelators, called siderophores. (hallmark being resistant to ceftazidime). These ESBLs These siderophores in Klebsiella belong to two different were, SHV-5 in Europe and TEM-10 & TEM-12 in the USA. groups. More common, the phenolate group with best known representative enterobactin, and hydroxamate The first report of carbapenemase-resistant Klebsiella type siderophores with best known representative, as pneumonia in the USA was in 1996. Since then it has been aerobactin and ferrioxamine.5 widely reported in various countries of Europe, South Some terms like hypervirulent Klebsiella pneumoniae America, and Asia. Carbapenemase produced may belong (hvKp) and hypermucoviscous K pneumoniae are also to Ambler class A (K pneumoniae carbapenemase) being used recently. hvKp was first recognized in Taiwan or class B (metallo-β-lactamases, MBL, New Delhi in 1986,6 although genomic studies suggest that it existed metallo-β-lactamases, NDM) and class D (OXA-48 like 9 unrecognized as early as 1920s.7 Approximately 70% of carbapenemases). hvKp isolates are capsular types K1 or K2. Fortunately less Polymyxins serve as a last resort for treatment in CRE. drug resistance has observed in hvKp. The siderophore, Lately resistance to polymyxins is being encountered all aerobactin accounts for more than 90% of hvKp’s total over the globe. Polymyxin resistance has been reported siderophore production. Clinical laboratories are unable as an independent marker for 14-day mortality in patients to differentiate between classical K pneumoniae and hvKp. with KPC producing K pneumoniae. Polymyxin resistance There is no commercially available assay that reliably is chromosomally mediated and takes place by addition differentiates the two. However, several biomarkers, of cationic groups to bacterial outer membrane. More including peg 344, iroB, iucA, MPa, mpA2, and quantitative recently a plasmid mediated gene (mcr-I) has been 10 siderophore production greater than30 mg/mL predict discovered, which confers resistance to polymyxins. hvKp strains.8 As per clinical laboratory standards institute/European Hypermucoviscous phenotypes may also show committee on antimicrobial susceptibility testing (CLSI/ increased virulence, as it may prevent them from host’s EUCAST) both microdilution should be used as a reference defense mechanisms. model for polymyxins susceptibility testing. The SENTRY11 and SMART study12 reported that in Role of Clinical Microbiology India, most common gene foe encoding carbapenemase was NDM-1 followed by OXA-48 variants. However, a study In isolates suspected to be carbapenemase producer from South India, done later reported equal distribution of Klebsiella, a double disc synergy test (DDST) on Muller- NDM-1 and OXA-48 like genes.13 Hinton agar media may be done. Tests using inhibitors such as boronic acid or EDTA are being used more frequently to detect KPC or Metallo Beta Lactamase (MBL) Treatment carbapenemase respectively. The modified carbapenem The worldwide spread of multidrug resistant Klebsiella inactivation method (Mcim) has replaced modified Hodge and KPC producing strains are causing a serious threat. test recently, as it is easy to perform and is less expensive. In our country resistance to various antibiotics is steadily Various automated systems may be employed to detect increasing. Problem is further aggravated by absence of a KPC producers. Various molecular methods, for example central collating body, ineffective antibiotic stewardship molecular antibiogram, have been used in identification of program, and rampant misuse of available antibiotics. pathogens and most common resistant genes. Molecular Major pharmacological companies are not doing enough

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research for discovering newer antibiotics. There is no available now. Eravacycline, a semi-synthetic tetracycline gold standard treatment for KPC producing Klebsiella. with efficacy against KPC and NDM carbapenemase, is The choice of treatment depends upon site and severity showing promise.15 of infection, local antibiogram, and host factors. Various strategies to effectively treat these infections are discussed Conclusion below. To conclude, the management of multidrug and pan-drug Combination Therapy resistant Klebsiella is a serious challenge to health care. Klebsiella is a major source of carbapenemase resistance in Most of the retrospective studies have found that various species through horizontal transfer of plasmids and combination therapy is associated with lower mortality. transposons, leading to emergence of multidrug and even Choice of the combination should be guided by local pan-drug resistance. We need good infection control program, antibiogram. For KPC producing Klebsiella, it will be antibiotic stewardship, environmental cleaning, hand hygiene, prudent to use polymyxins with carbapenems. However, and contact precautions to prevent spread of these deadly this combination may not show good results, if MIC levels bacteria. Tracing carriers of KPC Klebsiella and eradicating are more than 16 μg/mL. A study from ICU patients in through selective digestive decontamination may be an exciting option.16 North India showed polymyxins resistance in Klebsiella isolates in blood, urine, and sputum samples as 8.75%, 4.26%, and 4.4%, respectively.14 References . 1 WHO. Global Priority List of Antibiotic-Resistant Bacteria to Guide Dual Carbapenem Therapy Research, Discovery and Development of New Antibiotics. 2017;7. It refers to the use of ertapenem with either meropenem . 2 Kaur A, Gandra S, Gupta P, et al. Clinical outcome of dual colistin or doripenem. Ertapenem has highest affinity for and carbapenemase resistant Klebsiella pneumonia blood stream infection: a single centre retrospective study of 75 cases in India. carbapenemase and may consume most of it and allowing Am J Infect Control. 2017;45(11):1289-91. larger part of the other carbapenem to exert its bactericidal . 3 Veeraraghavan B, Shankar C, Karunasree S, et al. Carbapenem 15 effect. resistant Klebsiella pneumonia isolated from blood stream infection: Indian experience. Pathogens Global Health. 2017;111(5):240-6. Triple Combination Therapy . 4 Falagas ME. Deaths attributable to carbapenem resistant Enterobacteriaceae infections, Emerg Inf Dis J-CDC. 2014;20(7): Triple combination of polymyxins, carbapenem, and 1170-5. tigecycline has been found to significantly reduce the 5. Podschun R, Ullmann U. Klebsiella spp. As nosocomial pathogens: mortality in infections due to KPC producing Klebsiella epidemiology, taxonomy, typing methods and pathogenicity strains. The emergence of polymyxins resistant strains factors. Clin Microbiol Rev. 1988;11(4):589-603. during the treatment is a serious concern.15 . 6 Liu YC, Cheng DL, Lin CL, et al. Klebsiella pneumonia liver abscess associated with septic endophthalmitis. Arch Intern Med. 1986;146(10):1913-6. Newer Agents . 7 Lam MM, Wyres KL, Duchene S, et al. Population genomics of Avibactam is a non-beta-lactam beta-lactamase hypervirulent Klebsiella pneumonia clonal group 23 reveals inhibitor that has activity against class A and C beta- early emergence and rapid global dissemination. Nat Commun Forthcoming. 2018;9(1). lactamases including KPC and AmpC. Its combination . 8 Russo TA, Olson R, Fang CT, et al. Identification of biomarkers for with ceftazidime has been approved by FDA in 2015 for differentiation of hypervirulent Klebsiella pneumonia from classical complicated UTI including pyelonephritis. It may not be Klebsiella pneumonia. J Clin Microbiol. 2018;56(9):00776-18. effective if MIC levels are more than 8 μg/mL. Meropenem . 9 Reyes J, Aguilar AC, Caicedo A, et al. Carbapenem resistant with another beta-lactamase inhibitor vaborbactam is also Klebsiella pneumonia: microbiology key points for clinical practice. being tried. Imipenem-cilastatin along with relebactam, Int J Gen Medicine. 2019;12:437-46. 10. Calfee DP. Recent advances in the understanding and management another new beta-lactamase inhibitor is also being used. of Klebsiella Pneumoniae. 2017;6:1760. Plazomicin a new aminoglycoside with efficacy against 11. Castanheira M, Deshpande LM, Mathai D, et al. Early dissemination multidrug resistant Enterobacteriaceae bacteria is also of NDM-1- and OXA-181-producing Enterobacteriaceae in Indian

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hospitals: report from the SENTRY Antimicrobial Surveillance Program, 15. Oliva A, D’Abramo A, D’Agostino C, et al. Synergistic activity and 2006-2007. Antimicrob Agents Chemoth. 2011;55(3):1274-8. effectiveness of double carbapenem regimen in pan-drug resistant 12. Lascols C, Hackel M, Marshall SH, et al. Increasing prevalence and Klebsiella pneumonia blood stream infections. J Antimicrob dissemination of NDM-1 metallo-β lactamase in India: data from the Chemother. 2014;69(6):1718-20. SMART study (2009). J Antimicrob Chemother. 2011;66(9):1992-7. 16. Saidel-Odes L, Polachek H, Peled N, et al. A randomized double blind 13. Sharma A, Bakthavatchalam YD, Gopi R, et al. Mechanisms placebo controlled trial of selective digestive decontamination of carbapenem resistance in K pneumoniae and E coli from using oral gentamycin and oral polymyxin E for eradication of Bloodstream Infections in India. J Infect Dis Ther. 2016;4:293. carbapenem resistant Klebsiella carriage. Infect Control Hosp 14. Sodhi K, Mittal V, Arya M, et al. Pattern of colistin resistance in Epidemiol. 2012;33(1):14-9. Klebsiella isolates in an ICU of a tertiary care hospital in India. J Infect Public Health. 2020;13(7):1018-21.

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Infection with Acinetobacter—A 170 Challenge for the Physician

Krishna Padarabinda Tripathy

Abstract Acinetobacter species has emerged as one of the most significantly resistant pathogens causing heath-care associated infections. Acinetobacter baumannii, a Gram-negative coccobacillus constitutes 85% of the infections caused by Acinetobacter species in human beings. Prolonged length of hospital stay, invasive procedures, use of third-generation cephalosporins, etc. are some of the risk factors contributing toward the infection with this resistant organism. It has been increasingly recognized as an important cause of pneumonia, septicemia, meningitis, urinary tract, and wound infections and is associated with high mortality. Due to its inherently resistant property and aptitude to develop MDR and XDR strain, it has proven to be a therapeutic challenge for the physicians. This chapter highlights the infection and disease producing factors, mechanism of antibiotic class resistance and its treatment, and an unpublished data about A. baumannii in brief.

Introduction (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, A. baumannii, Pseudomonas aeruginosa, In the modern health-care system, Acinetobacter has and Enterobacter species) are known to effectively escape undoubtedly emerged as one of the most significant the outcome of antibacterial drugs. A. baumannii is pathogens accountable for health-care associated amongst the most serious ones in the group. This Gram- infections involving multiple organs. It is also known negative coccobacillus because of its inherent mechanism to cause community acquired infections in combat of resistance and pathogenicity has become a threat to zone and disaster associated infections because of its mankind and one of the significant therapeutic challenges ubiquitous nature. In 1911, Acinetobacter species were for the physicians. isolated from soil and first described as Micrococcus calcoaceticus. Thereafter, the genus was renamed multiple times for several years, and since 1950, it is referred as Bacteriology Acinetobacter. Earlier Acinetobacter was an organism of These species are strictly aerobic, Gram-negative, unconvincing pathogenicity, which during the last three non-motile, oxidase negative, catalase positive, non- decades has emerged as a serious infectious agent to the fermenting coccobacillus that grows at 20–30°C and hospitals around the globe. could be easily recovered on standard culture media. According to many studies worldwide, it has been Amongst the Acinetobacter species causing infections in found that Acinetobacter baumannii develops resistance human beings, A. baumannii constitutes about 85% of the to antimicrobials rapidly, resulting in multidrug-resistant infections in humans. Other species in the genus causing and pan-drug-resistant strains, which may cause large occasional infections in human beings are Acinetobacter outbreaks of health-care associated infections. The World nosocomialis, Acinetobacter pittii.1 Molecular methods like Health Organization declared that the ESKAPE organisms Matrix assisted laser desorption-ionization-time-of-flight

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Risk factors for colonization and infection with the Virulence factors and their role in pathogenesis of TABLE 1 TABLE 2 pathogen A. baumannii

Risk factors for colonization and infection with A. baumannii Virulence factors Role in pathogenesis Health-care associated zz Prolonged length of hospital/ICU stay Porin (OmpA, Omp33-36, Adherence and invasion, induction of infections in ICU zz Mechanical ventilation Omp22, CarO, Opr D-like) apoptosis, biofilm formation zz patients Invasive procedures Capsular polysaccharide Growth in serum, prevent complement zz Tracheostomy, central venous activation and delays phagocytosis, catheterization biofilm formation zz Nasogastric tube feedings zz Recipient of third-generation Lipopolysaccharide (LPS) Serum resistance, survival in tissue cephalosporins, fluoroquinolones, and infection, evasion of the host immune carbapenems response Health-care associated zz Hands of the health-care worker Phospholipase (PLC and Exert cytotoxic effect on epithelial cells infections in hospital zz Respiratory therapy equipment PLD) and facilitate their invasion zz Infusion pumps Iron-acquisition systems Ability to grow in iron deficiencies zz Fomites like bed rails, door handles, in human host through secretion of tabletops siderophores Community-acquired zz History of alcohol abuse infections zz Diabetes mellitus zz Smoking causing hospital-acquired infections after Pseudomonas zz Chronic lung disease, Chronic kidney disease species (52%). A. baumannii was found resistant to zz Cancers most antibiotics except colistin, it showed 70% non- susceptibility to almost every antibiotics tested. Invasive specimens from lower respiratory tract and blood had mass spectrometry (MALDI-TOF-MS) and quantitative higher non-susceptibility rates against different categories real-time polymerase chain reaction (RT-PCR) are often of antibiotics in comparison to other specimens.4 required to detect A. baumannii because it is difficult to identify it just based on phenotype. Acinetobacter species that have been isolated from Pathogenesis foods, arthropods, the environment, soil, and water are A. baumannii intrinsically is more virulent in humans known to be its natural habitats. In our day-to-day practice, as compared to other Acinetobacter spp. as it grows Acinetobacter culture positivity should be analyzed as better at 37°C and resists macrophage uptake than other colonization which is the presence of bacterium on a species. The important virulence factors and their role in body surface (like on the skin, oral cavity, airway, or pathogenesis is summarized in the Table 2. intestines) and not causing disease in the individual, in contrast to infection, where there is invasion of a host’s Mechanism of Resistance body tissues by disease-causing organisms. There are Acinetobacter infections have proven to be a therapeutic various risk factors for colonization and infection with the challenge to physicians as it is one of the most resistant pathogen that is summarized in Table 1. It is hypothesized organisms known and its treatment centers upon that A. baumannii species are ubiquitous in nature2 as controlling the antibiotic resistance. It is an inherently they survive in dry as well as damp environment which resistant organism which has the aptitude to develop promotes its environmental desiccation for weeks and multidrug-resistant and extensive drug-resistant strains. causes fomite contamination in hospitals. This is one of the vital contributory factors in its capability In the United States, the Centre for Disease Control to adapt itself to changes in environmental pressures. have estimated 12,000 Acinetobacter infections every The common mechanisms of resistance are explained in year out of which multidrug-resistant strains causes Figure 1. 7,300 cases with high mortality.3 The Indian Council of Medical Research estimates Acinetobacter species AmpC cephalosporinase: Acinetobacter-derived as the second most common isolated pathogen (45%) cephalosporinases (ADCs) are the genomic variants of A.

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Fig. 1: Mechanism of resistance in Acinetobacter baumannii

baumannii which contains a non-inducible chromosomal „„ Serine and metallo-β-lactamases: It confers resistance AmpC cephalosporinase. Addition of promotor insertion to carbapenems as they as they exhibit strong sequence known as ISAba1 regulates the AmpC hydrolytic activity against all β-lactam antibiotics gene. Overexpression of AmpC cephalosporinase/ except monobactams (i.e., aztreonam). Aminoglycoside modifying enzyme (AME) and the „„ DNA topoisomerase mutations: Resistance to presence of ISAba1 is intrinsically responsible for resistance aminoglycosides and quinolones in Acinetobacter to extended spectrum cephalosporin. Antibiotics like infections is due to the point mutations in the gyrA and Cefepime and carbapenems, so far seems to have a stable parC topoisomerase enzymes which are the bacterial response to these enzymes. targets. „„ Porin channels: Amongst the list of various mechanisms „„ PmrA and PmrB proteins: Due to its overexpression, causing carbapenem resistance, the commonest resistance to colistin occurs. are absence of penicillin binding protein 2(PBP2) 5 and production of naturally occurring oxacillinase Definitions in Antimicrobial Resistance (OXA). Some isolates have been observed to have „„ Multidrug resistant (MDR): When the isolate is added downregulation of porin expression, leading to resistant to at least three classes of antimicrobial drugs, reduction in entry of carbapenem. that is, all penicillin and cephalosporins (including „„ Efflux pumps: Overexpression of bacterial efflux inhibitor combinations), aminoglycosides and pumps decreases the concentration of β-lactam fluoroquinolones, it is said to be “MDR Acinetobacter antibiotics in the periplasmic space. Efflux pumps species.” usually act in association with overexpression of AmpC „„ Extensively-drug resistant (XDR): When the β-lactamases or carbapenemases causing resistance in Acinetobacter isolate is resistant to carbapenems and Acinetobacter. Efflux pumps not only remove β-lactam shall also be resistant to three classes of antimicrobials antibiotics, but can actively remove chloramphenicol, mentioned above (MDR), it is said to be “XDR quinolone, tetracycline, tigecycline, and disinfectants. Acinetobacter species.”

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„„ Pan-drug resistant (PDR): When the XDR Acinetobacter Urinary Tract Infections isolate is also resistant to tigecycline and polymyxin, it 6 Health-care associated urinary tract infection which is is said to be “PDR Acinetobacter species.” a major source of A. baumannii isolates occur mainly as catheter-associated infections or with percutaneous Clinical Manifestations nephrostomy tubes. Community-acquired A. baumannii Pneumonia urinary tract infections are reported in post-renal Nosocomial pneumonias occur due to aspiration, transplant and nephrolithiasis patients. prolonged hospital stay, and mechanical ventilation, which create an ideal environment for transmission of Other Miscellaneous Infections bacteria like Acinetobacter. It adheres and forms biofilms Meningitis: Majority of the cases of A. baumannii on the tube. The clinical manifestation is fever and meningitis have been reported in post-traumatic injuries increased sputum production. It is diagnosed through and post-neurosurgical procedures. respiratory cultures. Imaging findings are non-specific Osteomyelitis: Occurs typically postsurgical or trauma and can include lobar consolidations, pleural effusion, or related. Acinetobacter can cause keratitis due to use of rarely cavitation. contact lenses, and few cases of native and prosthetic valve Community-acquired pneumonia is not as common as endocarditis have been reported. nosocomial pneumonia but a serious manifestation when caused by A. baumannii. Majority occurs in regions with Our institutional experience (unpublished): In our institute hot and humid climates. It is caused by a diverse range of KIMS Bhubaneswar, a recent study was done for 1 year strains and is distinct from hospital strains. Symptoms and (July, 2018–June, 2019). Around 455 patients grew A. signs are similar in both the types. Without appropriate baumannii infection in various cultures, out of which 348 initial antibiotic therapy, mortality rate has been reported (76.4%) found in ICU patients and 107 (23.6%) in non-ICU to be as high as 64%.7 patients. Respiratory tract infection was the commonest infection in ICU as well as non-ICU settings, followed by Bloodstream Infections septicemia in ICU and skin and soft tissue infection in Bloodstream infections due to A. baumannii occur non-ICU settings. In ICU setting, 8% of isolates were pure mostly in the presence of central venous catheter or due MDR, 68% were XDR, 7% PDR, and 17% were sensitive to to dissemination secondary to extensive pneumonia. all classes of antibiotics while in non-ICU patients, 14% Patients may present with septic shock and disseminated of isolates were pure MDR, 52.3% XDR, 9% PDR, and 24% intravascular coagulopathy. were sensitive to all classes of antibiotics. This states the seriousness of infections caused by MDR and XDR A. Skin and Soft Tissue Infections baumannii organisms in a health-care setting and the Acinetobacter species are known to colonize the skin spread of pan drug resistance even in non-ICU areas. flora and it is important to differentiate colonization Figure 2 depicts the pattern of drug resistance as per the from nosocomial infections. Trauma-associated A. isolates obtained from different site of infections. baumannii skin and soft tissue infections may be due to orthopedic external fixator devices, gunshot wounds, Treatment etc. There have been several recent reports regarding the Acinetobacter is considered amongst the most resistant occurrence of necrotizing fasciitis due to A. baumannii. organisms and initiating effective empirical therapy is The skin infection due to this species may evolve from an challenging to the physicians. Definitive therapy should be edematous peau d’orange appearance to sandpaper like, based on antimicrobial susceptibility test results. to a necrotizing process with hemorrhagic bullae. In war-zones or after a traumatic injury to soldiers, Empirical Therapy Acinetobacter has been a significant cause of skin & soft Antibiotic susceptibility pattern is an important factor, tissue infections. These infections are also found following which guides clinicians regarding the therapy in an natural disasters (floods, earthquakes, etc.). intrinsically resistant organism. In A. baumannii

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Minocycline therapy has high treatment success once given in combination therapy. Aminoglycosides (amikacin and tobramycin) are not of abundant use against A. baumannii due to its toxicity and lack of lung penetration. Inhaled tobramycin can be an adjunct as inhalational therapy in A. baumannii pneumonia. Polymyxins (Colistin and Polymyxin B) being a cationic detergent disrupts bacterial cytoplasmic membranes. It was previously abandoned for its nephrotoxicity and neurotoxicity. Currently the nephrotoxicity rates are reportedly 36%, and neurotoxicity is rarely seen these days due to modified formulations. Although the dosage Fig. 2: Pattern of drug resistance in A. baumannii infection differs from patient-to-patient, polymyxin can be given in ICU and non-ICU patients at the dose of 1.5–3 mg/kg q12h in MDR-Acinetobacter infections. infections, empirical therapy is advisable to initiate Colistin can be given inhalational and intravenous with carbapenems, as the probability of A. baumannii route. For combination therapies, colistin is a key being resistant to cephalosporins (a common first-line component. An important side effect of inhalational antibiotics) is more. After the sensitivity reports therapy is colistin is bronchoconstriction. modified accordingly. The rising rates to resistance are to the last-line drugs, that is, tigecycline and polymyxin against A. baumannii Treatment of MDR Acinetobacter Species are highly reported and is of substantial concern. There is Here the preferred drugs are Carbapenems, if susceptible.8 a critical need to find alternative therapeutic options for Usually, imipenem is given at the dose of 500 mg q6h and this. meropenem at the dose of 2g q8h. The prolonged infusion Combination antimicrobial therapy: Combination therapy over 3–4 hours is better than bolus injections. appears to be promising in prevention of emergence of resistance and in improving clinical outcomes. Its key Treatment of Extensive and Pan-drug component to treat MDR A. baumannii is Colistin. Many Resistant Acinetobacter Species colistin-based combined therapies, including colistin- The resistance rates of carbapenems in A. baumannii rifampicin, colistin-minocycline, colistin-carbapenem, infections have been rising substantially globally. However, colistin-sulbactam have been found to act synergistically there is no consensus suggesting optimal anti-microbial in vivo or in vitro against A. baumannii. treatments for such strains. The options available are: Although polymyxin causes dose-related nephro­ Tigecycline is a glycylcycline antibiotic and is another drug toxicity, Polymyxin B combination therapies when used that can be used clinically against MDR A. baumannii; with amplified doses of antibiotics such as carbapenem, Tigecycline is usually found to have a low MIC (2 g/mL) minocycline, and tigecycline have been found to attenuate for A. baumannii strains, the serum concentration of the the development of polymyxin resistance. drug is also low, and the outcome of ventilator-associated pneumonia and bacteremia associated with A. baumannii Future treatment options: In view of increasing rates of clinical trials have shown inferior results compared to emergence of multidrug resistance and lack of newer other alternative agents. class of antibiotics, alternative strategies are in pipeline to Minocycline is a tetracycline that has good control and treat A. baumannii. antimicrobial activity and it may even act against the strains „„ Bacteriophage: Bacteriophages therapy is being re- resistant to other tetracyclines (including tigecycline). evaluated as an alternative management option to Cross-resistance has been reported with minocycline. help counteract antibiotic resistance due to its high

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Fig. 3: Source of infections and the control measures to prevent infections

specificity and ability to work quickly. Examples—vB_ 8 of resistance of A. baumannii infections, it is important to Ab-M-G7 and B#-C62 for MDR A. baumannii. promote rationale use of antibiotics, and take adequate control „„ Cathelicidins: (antimicrobial peptides): There were measures to prevent the establishment of drug resistant positive results from a cathelicidin known as “Tammar endemic strains. Wallaby WAM1.” It has a probability for parenteral use in Acinetobacter infections in humans. „„ Radioimmunotherapy: It is emerging as a therapeutic References possibility due to its ability to kill microorganisms as . 1 Touchon M, Cury J, Murphy C, et al. The genomic diversification effectively as cancer cells.9 of the whole acinetobacter genus: origins, mechanisms, and „„ Photodynamic therapy: A photosensitizer is topically consequences. Genome Biol Evol. 2014;6(10):2866-82. applied into the infected tissue, followed by red or . 2 La Scola B, Raoult D. Acinetobacter baumannii in human body louse. Emerg Infect Dis. 2004;10(9):1671-3. near infra-red illumination is given which penetrates . 3 Bulens SN, Wilson L, Reno J, et al. Carbapenem-nonsusceptible and kill the infected tissue. It is used to treat localized Acinetobacter baumannii, 8 US Metropolitan Areas, 2012–2015. bacterial infections. Emerg Infect Dis. 2018;24(4):727-34. „„ Nanoparticle technology: This novel and inexpensive . 4 Walia K, Ray P, Kapil A, et al. Establishing antimicrobial resistance technology9 has shown effective results with its stable surveillance & research network in India: journey so far. Indian J nitric oxide-releasing nanoparticle platform and it Med Res. 2019;149(2):164-79. . 5 Manchanda V, Sanchaita S, Singh N. Multidrug resistant is potential option for treatment of A. baumannii acinetobacter. J Glob Infect Dis. 2010;2(3):291-304. induced complex cutaneous infections. . 6 Dexter C, Murray GL, Paulsen IT, et al. Community-acquired Acinetobacter baumannii: clinical characteristics, epidemiology Infection Control and Prevention and pathogenesis. Expert Rev Anti Infect Ther. 2015;13(5):567-73. 7. Kusradze I, Murray GL, Peleg AY, et al. Characterization and testing Source of infections and the control measures to prevent the efficiency of Acinetobacter baumannii phage vB-GEC_Ab- infections is summarized in Figure 3. M-G7 as an antibacterial agent. Front Microbiol. 2016;7:1590. . 8 McConnell MJ, Docobo-Pérez F, Pachón J, et al. Vaccination with Conclusion outer membrane complexes elicits rapid protective immunity to multidrug-resistant Acinetobacter baumannii. Infect Immun. Acinetobacter species have emerged as one of biggest 2011;79(1):518-26. challenge to physicians because of its inherent resistant . 9 Friedman AJ, Han J, Chacko M, et al. Sustained release nitric strains and ability to cause extensive resistance to even the oxide releasing nanoparticles: characterization of a novel delivery newer antimicrobials. To decrease the spread and emergence platform based on nitrite containing hydrogel/glass composites. Nitric Oxide. 2008;19(1):12-20.

MU-170.indd 1116 29-01-2021 15:06:26 CHAPTER Scrub Typhus—Clinical Manifestations and 171 Management

Sudhir Kumar, Govind Kumar, Arshad Ahmad, Amit Kumar Mishra

Abstract Scrub typhus is an arthropod born acute infectious disease that is caused by intracellular Gram-negative organism Orientia tsutsugamushi. This disease is mainly reported from states of the Himalayan terrain, Eastern and Western Ghats, and the central part of India. Scrub typhus is transmitted by some species of trombiculid mites which are found in areas of heavy scrub vegetation. The mites feed on infected rodent hosts and subsequently transmit the parasite to other rodents and humans. The main target tissue of O. tsutsugamushi is the vascular endothelium in human, leading to generalized vasculitis and perivascular inflammatory changes, and results in end-organ damage of many vital organs including nervous system, cardiovascular system, kidney, lung, and other organ. Scrub typhus presents with fever, headache, myalgia, cough, abdominal pain, conjunctival redness, altered consciousness, apathy, shin pain, lymph node enlargement, hepato- splenomegaly, macula-papular rash and eschar. Currently, the drug of choice for treatment of scrub typhus is doxycycline. Other drugs used to treat scrub typhus, includes tetracyclines, chloramphenicol, rifampicin, azithromycin and quinolones.

Introduction the Russia in the north. The disease is mainly prevalent to south-eastern and eastern parts of Asia including Scrub typhus is an arthropod born acute infectious India, Myanmar, Nepal, Sri Lanka, Thailand, and other disease that is transmitted to humans by Trombiculidae areas in the region.2 More than hundred crore people of family. It is caused by intracellular Gram-negative organism Orientia tsutsugamushi. This disease was first world are at risk for scrub typhus and an estimated ten 3 described in 1899 in Japan. People of all ages are affected lakhs cases occur annually. In India, scrub typhus is by this disease including those at extreme of age. The reported from states of the Himalayan terrain, Eastern term “scrub” is related to the vegetation (land between and Western Ghats and the central part of India. Number woods and clearings) where vectors are proliferating. of Leptotrombidium deliense is affected by rainfall, which The name scrub typhus is misleading, as the disease can may be the cause for a higher case during the Monsoon 4 be contracted in many other habitats, including forest, time as shown by Gurung et al. In India, the agent of beaches, large gardens, and plantations. The word scrub typhus is O. tsutsugamushi. Its antigenic structure “typhus” is a Greek word which means “fever with stupor” is different from other Rickettsiae. Although our country or smoke.1 “Tsutsuga” means small and dangerous and India is a part of tsutsugamushi triangle, Scrub typhus “mushi” means insect. grossly remains under diagnosed owing to the non- Scrub typhus is mainly distributed in the tsutsugamushi specific variable clinical presentation except eschar, poor triangle, which is bounded by Australia in the south, Japan specific diagnostic facility and very low index of suspicion in the east, Afghanistan in the west and southern parts of by the physician.

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Vector and Host L. deliense and L. akamushi are the main vectors of scrub typhus, which are found in countries of the Southeast Asian region including India. This disease is spread through the larval mites or “chiggers.” The natural hosts for scrub typhus are small rodents including Rattus subgenus. The field rodents and the vector mites act as a reservoir and because of these two the infection continues in nature.

Transmission and Pathogenesis The causative organism of scrub typhus is O. tsutsugamushi, which is an intracellular Gram-negative bacterium. Humans are accidental hosts and the infectious agent is transmitted through the skin by the bite of larval Fig. 1: Eschar at axilla stage of infected trombiculid mites or chiggers.5 Disease occurrence is more in rainy season and commonly seen discomfort. Patients may present with subacute/chronic among persons who engage in occupational or other work 9 related to contact with mite-infested area. The mites have pyrexia and fever of unknown origin. The severity of the symptoms varies widely, depending on the strain of a life cycle of four stages: adult, egg, larva and nymph. organism and condition of the host. Only stage that can transmit the disease to humans is A small vesicular lesion at the chigger feeding site is the chigger or larva. The chigger takes up tissue fluid and usual first sign of scrub typhus, which usually changes into lymph. Very high number of O. tsutsugamushi are there in an eschar or an ulcer with local lymph node enlargement. the salivary glands of the chigger and these are transmitted An eschar is a typical lesion with black necrotic center and into their host when they take up tissue fluid.6 an erythematous border and is mainly located in the groin, Transovarial transmission is seen in mite where they axilla, genitalia, and neck (Fig. 1). The eschar is found in pass the infection on to their eggs. Likewise, transstadial patients suffering from scrub typhus ranges from 7% to transmission is also seen in which the infection transmitted 80% in different study. Eschar is the single most important from egg to the chigger and adult. clue for diagnosis on physical examination. The detection The strain of organism and condition of the host are rate of eschar depends on multiple factors like the skin two most important factors that decide the severity of color of the infected person and site of the lesion. disease. The pathophysiology of scrub typhus is not fully Sudden onset fever is the most common symptom understood, though in general it is thought to be due to accompanied with conjunctival redness, severe headache, vasculitis either localized or disseminated. The principal altered consciousness, apathy, myalgia, shin pain, and target site of O. tsutsugamushi is the vascular endothelium more characteristically lymph node enlargement and in human. This organism acts at vascular endothelial hepatosplenomegaly. Fever is usually of high grade and cells leading to generalized vasculitis and perivascular may be with shaking chills. inflammatory changes, and results in end-organ damage A maculopapular rash appear at end of first week of many vital organs.7 Both humoral and cellular immune which initially seen at the trunk and later on spread to response are seen against O. tsutsugamushi. the limbs. This rash is not well appreciated among dark skinned individuals. Clinical Features Systemic symptoms and signs related to major organ The average incubation period of O. tsutsugamushi in system like the central nervous system, cardiovascular humans is around 10 days and can vary between 6 and system, kidney, pulmonary, and digestive systems become 21 days.8 Main symptoms of scrub typhus are pyrexia, evident by end of second week. Major organ system headache, muscle pain, dry cough, and abdominal involvement may produce serious complication in the

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form of myocarditis, pneumonia, meningitis/encephalitis, to perform.13 After infection IgM antibodies against O. acute renal failure, and gastrointestinal bleeding. Acute tsutsugamushi appear in the body at the end of first week respiratory distress syndrome development is more while IgG antibodies appear at the end of the second week. commonly seen in patients of scrub typhus who have The Weil-Felix (WF) test has better specificity but poor high leukocyte count and late treatment. Meningitis, sensitivity and is based on the identification of antibodies meningoencephalitis, or encephalitis is common form of to various Proteus species, which contain cross-reacting neurological involvement seen in scrub typhus.10 antigenic epitopes to antigens from members of the genus According to Kim et al., older age (≥60 years), scrub Rickettsia. The WF test is said to be positive when there is typhus patients without an eschar, and laboratory high titer of 1:320 or more or a fourfold rise in titer. parameters such as leukocyte counts >10,000/mm and The standard serological test is the indirect IFA for the serum albumin level ≤3.0 g/dL are potential indicators detection of IgM antibodies. This test has many demerit of complications.11 Untreated patient remains febrile for which consist of retrospective nature, availability of trained about 2 weeks and have a long convalescence of around 6 technician and equipment which may not be possible in weeks thereafter. many labs.14 At present most lab use the enzyme-linked immunosorbent assay (ELISA) for the presence of IgM Differential Diagnosis antibodies in scrub typhus as it gives an objective result and has sensitivity almost equal to that of IFA.13 Rapid Differentiated and undifferentiated fever are two form of diagnostic kit to detect scrub typhus IgM antibodies have acute febrile illness (AFI). In differentiated fever there is sensitivity in range of 34.7–96.7% and specificity between obvious presence of focus of infection or inflammation, 93.3–99.7%.15 while in undifferentiated fever there is no obvious focus The samples from which causative microbe of scrub of infection and the symptoms and signs are quite typhus is isolated are buffy coat of blood, defibrinated nonspecific. In patient with undifferentiated fever several whole blood, plasma, tissue, skin biopsy, and arthropod diagnostic possibilities are considered, especially in samples. It takes around 4 weeks to detect rickettsia in 12 the tropics. The differential diagnosis of scrub typhus cell culture. Molecular methods using PCR is possible includes typhoid fever, dengue fever, malaria, other from skin rash specimen, eschar, lymph node biopsies, or rickettsioses, anthrax, leptospirosis, and hemorrhagic blood and is less time consuming. Nested PCR method is fevers. It is considered as one of the causes of fever of more sensitive than doing single PCR. This is a less time- unknown origin (FUO) in endemic areas. consuming method and takes around 1 day.16 A positive IgM ELISA in the suspected patient with Diagnosis defervescence within 2 days of prescribing doxycycline or scrub IgM ELISA seroconversion on convalescent sera Febrile illness along with eschar on physical examination with other causes of acute febrile illness ruled out after almost confirms the diagnosis. Leukocytosis and decreased proper investigations also favors scrub typhus infection.12 platelet count may be seen. Altered liver function and kidney function test may be seen in large number of cases. Ultrasonography may reveal hepatosplenomegaly. Management The lab diagnosis of scrub typhus is either confirmed There are several drugs to treat scrub typhus, including or supported by identifying the microbe in cell culture, tetracyclines, chloramphenicol, rifampicin, azithromycin, presence of antigen by immune-histochemical methods and quinolones. Currently, the drug of choice or the antibodies by the indirect immunofluorescence is doxycycline, a member of the tetracycline family, assay (IFA) and detecting organism’s nucleic acid using and several studies have proved its effectiveness. The polymerase chain reaction (PCR). recommended therapeutic dose for scrub typhus in adult As antigen identification tests have low sensitivity/ is doxycycline 200 mg/day for 7–15 days and tetracycline specificity and require tissue specimens, serological 2 g/day for 7–15 days in divided doses. But many case tests to identify antibodies are the better diagnostic reports of natural resistance make it difficult to prescribe tool in real clinical scenario as they are simple and easy suitable antibiotic.17 The use of azithromycin in pregnant

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women is believed to be safe for both mothers and fetuses, . 4 Gurung S, Pradhan J, Bhutia PY. Outbreak of scrub typhus in the and it is classified as category B by the US FDA Pregnancy North East Himalayan region-Sikkim: an emerging threat. Indian J Category. Azithromycin is an effective drug for the Med Microbiol. 2013;31(1):72-4. . 5 Aggrawal P, Mahesh DM, Kaushal SS, et al. Atypical eschar sites in management of scrub typhus as it efficiently penetrates scrub typhus in sub-himalayas. JAPI. 2009;57:153. human white blood cells and macrophages, which are 6. Suputtamongkol Y, Suttinont C, Niwatayakul K, et al. Epidemiology target area for of O. tsutsugamushi. It should be given as and clinical aspects of rickettsioses in Thailand. Ann N Y Acad Sci. short course because of its longer half-life.18 2009;1166(1):172-9. Chloramphenicol can also be given in adults and its . 7 Dumler JS, Siberry GK. Scrub typhus (Orientia tsutsugamushi). In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF (Eds). Nelson dose is 500 mg qid orally for 7–15 days. Rifampicin is also Textbook of Pediatrics. Part XVI. 18th edition. Section 11. Ch. 226. effective against O. tsutsugamushi. Vol. 57. Philadelphia: Saunders, Elsevier; 2007. 2013. pp. 1295-6. Doxycycline is the drug of choice for prophylaxis and 8. Rajapakse S, Rodrigo C, Fernando D. Scrub typhus: pathophysiology, the usual prophylactic dose is 200 mg per week. Killed clinical manifestations and prognosis. Asian Pac J Trop Med. vaccines against scrub typhus was disappointing because 2012;5(4):261-4. of results in human studies were not as successful as they . 9 Saah AJ. Orientia tsutsugamushi (scrub typhus). In: Mandell GL, Bennett JE, Dolin R (Eds). Principles and Practice of Infectious were in animal studies. Disease, 5th edition. Philadelphia, PA: Churchill Livingstone; 2000. pp. 2056-7. Current Status in India 10. Misra UK, Kalita J, Mani VE. Neurological manifestations of scrub typhus. J Neurol Neurosurg Psychiatry. 2015;86(7):761-6. Earlier Scrub typhus was an endemic disease in many 11. Kim DM, Kim SW, Choi SH, et al. Clinical and laboratory findings pockets of our country. But because of large scale use of associated with severe scrub typhus. BMC Infect Dis. 2010;10:108. insecticidal later, scrub typhus cases were reported in 12. Chrispal A, Boorugu H, Gopinath KG, et al. Acute undifferentiated very low number from India. Recently there had been febrile illness in adult hospitalized patients: the disease spectrum increase in number of cases of scrub typhus in India. and diagnostic predictors—an experience from a tertiary care hospital in South India. Trop Doct. 2010;40(4):230-4. Resurgence may be due to changes in the human behavior, 13. McDade JE. Rickettsial diseases. In: Hausler WK, Sussman M (Eds). unplanned urbanization, and deforestation, which result Topley & Wilson’s Microbiology & Microbial Infections. London: in displacement of vectors as well host rodents. Human Arnold; 1998. pp. 995-1011. in town may get bitten by the disease-causing mite larvae 14. Paris DH, Shelite TR, Day NP, et al. Unresolved problems related to while moving in parks or during any other recreational scrub typhus: a seriously neglected life-threatening disease. Am J activities such as camping in the affected vegetation area.19 Trop Med Hyg. 2013;89(2):301-7. 15. Blacksell SD, Jenjaroen K, Phetsouvanh R, et al. Accuracy of AccessBio Immunoglobulin M and Total Antibody Rapid Conclusion Immunochromatographic Assays for the Diagnosis of Acute Scrub Typhus Infection. Clin Vaccine Immunol. 2010;17(2):263-6. Scrub typhus is an important differential diagnosis of 16. Murai K, Tachibana N, Okayama A, et al. Sensitivity of polymerase undifferentiated fever cases. Eschar is most important clinical chain reaction assay for rickettsia tsutsugamushi in patients’ blood sign. High index of suspicion is needed to diagnose it as India is samples. Microbiol Immunol. 1992;36(11):1145-53. a part of endemic zone “Tsutsugamushi triangle”. 17. Walker DH, Dumler JS, Marrie T. Rickettsial diseases. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J (Eds). Harrison’s Principle of Internal Medicine. Part 8. 18th edition. References Section 10. Ch. 174. USA: The McGraw-Hill Companies; 2012. pp. 1. Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin 1064-5. Infect Dis. 2003;16(5):429-36. 18. Frenck RW Jr, Mansour A, Nakhla I, et al. Short-course azithromycinfor . 2 Frequently Asked Questions-Scrub Typhus WHO. [Last accessed the treatment of uncomplicated typhoid fever in children and on 2017 Aug 13]. Available from: http://www.searo.who.int/entity/ adolescents. Clin Infect Dis. 2004;38(7):951-7. emerging_diseases/CDS_faq_Scrub_Typhus.pdf 19. Laskar AR, Suri S, Acharya AS. Scrub typhus: re-emerging public 3. Mahajan SK. Scrub typhus. J Assoc Physicians India. 2005;53:954-8. health problem in India. J Commun Dis. 2015;47(3):19-25.

MU-171.indd 1120 29-01-2021 15:05:46 CHAPTER

172 Burkholderia Species

Shubhransu Patro

Abstract Burkholderia species contain the most versatile organisms that occupy a surprisingly wide variety of ecological niches. These infections can be very difficult to treat and, in some cases, lead to death as it is considered to be one of the most antimicrobial- resistant organisms found in the clinical laboratory. These bacteria are used for the purpose of biocontrol, bioremediation, and promotion of plant growth, but safety issues regarding human infections, particularly in patients with compromised immunity, are still questionable. This chapter provides an overview of the genus Bukholderia, its ecological diversity, the clinical manifestations observed, and the management protocols that will guide the physician to effectively treat this infection.

Introduction onion bulb at Cornell University in the year 1950 and was named as Pseudomonas cepacia.1 In the year 1992, Burkholderia species continues to be one of the notorious Yabuuchi et al. created a new genus “Burkholderia,” and multidrug resistant organisms among the nonfermenting transferred P. cepacia and six other species belonging gram-negative bacilli (NFGNB). First described by to rRNA group II of the genus Pseudomonas under the William Burkholder, the species majorly include plant new genus.5 Since the discovery, the taxonomy of the pathogens and soil bacteria with two important exceptions, new genus has undergone considerable changes and Burkholderia mallei and Burkholderia pseudomallei, which presently the genus Burkholderia consists of 22 species.6 are known to be notorious pathogens in humans and All the members of the species possess a very large animals.1,2 Apart from being a primary pathogen in patients genome ranging between a size of 6 and 9 Mb, which of Cystic fibrosis (CF), Burkholderia cepacia complex renders the organism versatile and ubiquitous. In the (BCC) has been found responsible for bacteremia in subsequent years, Vandamme and colleagues described immunocompromised and chronically debilitated patients. Burkholderia cepacia as a complex of closely related There have been numerous documented outbreaks of BCC genomovars and genomic species and referred them septicemia in intensive care units and patients with renal collectively as BCC, which included ten different unique failure.3 Similarly, B. mallei and B. pseudomallei have been species. The members of the BCC are B. cepacia, B. reported as the causative agent of diseases known to be multivorans, B. cenocepacia, B. stabilis, B. vietnamiensis, Glanders and Melioidosis, respectively, both of which carry B. dolosa, B. ambifaria, B. anthina, B. pyrrocinia, and B. significant mortality and morbidity.4 ubonensis.2 Based on comparative 16S ribosomal RNA and recA sequencing, multilocus sequence typing (MLST), and Taxonomy intermediate DNA-DNA binding values, recently seven William Burkholder, an American microbiologist, first novel species of Burkholderia have been identified and discovered the organism responsible for bacterial rot of are proposed to be included under BCC.7 The seven new

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members are; B. latens, B. diffusa, B. arboris, B. seminalis, deteriorate due to necrotizing pneumonia and sepsis, B. metallica, B. contaminans, and B. sabiae. which may result in death.13 This fatal clinical decline in patients with CF is known as “Cepacia Syndrome” and Epidemiology it has not been observed with any other pathogens. This explains the varied outcomes amongst CF patients who are The ability of Burkholderia species to survive in extreme infected with same strain. Reports of “Cepacia Syndrome” environmental conditions makes it ubiquitous. Because have also been documented in non CF patients.14 There of minimal nutritional requirements, it can survive for has been reported mortality of 75% in patients with CF months in media and solutions like antiseptics, sinks, who undergo transplantation.15 water, and intravenous fluids. They also tend to reside on indwelling catheters, IV cannula, and nebulizers.8 Commercial use of BCC in agriculture as a biocontrol BCC Infection in Non-CF Patients agent, in the bioremediation of toxic agents and plant BCC is recognized as an important pathogen in patients growth promotion contributed to the increased incidence suffering from chronic granulomatous disease where there of human infection by the organism. Various reports have is inability of macrophages to produce reactive oxygen documented person-to-person transmission by a few species due to mutations in NADPH oxidase complex. strains of BCC and B. pseudomallei.9 Studies have shown Mostly, it is a nosocomial infection via contaminated that by the age of 18 years, 3.5% of patients suffering from hospital equipment like disinfectants, antiseptics, topical CF harbor BCC.10 Among all other Burkholderia species, anesthetics, and respiratory therapy equipment. BCC BCC is the most frequently isolated clinical pathogen bacteremia in non-CF hospitalized patients is most often followed by B. mallei and B. pseudomallei. B. pseudomallei, seen in patients with comorbidities such as diabetes the causative agent of Melioidosis, is predominantly found mellitus, congestive heart failure, malignancy, and in the regions of Asia, Africa, Northern Australia, and hemodialysis along with indwelling urinary catheters, South America and is isolated from soil and water. It is also central venous catheters, and endotracheal tubes. BCC known to cause outbreaks in Thailand causing significant pulmonary infection is mostly observed in intensive care mortality and morbidity. B. mallei also share the same patients who are on prolonged mechanical ventilation 16 geographical territories as B. pseudomallei and primarily (Fig. 1). Besides this, skin, soft tissue, and genitourinary affects horses, causing equine glanders. It was one of infection have been reported in patients with burns the first used agent as biological weapon by Germany or surgical wounds, after prostate biopsy, urethral in the World War I.11 Human transmission occurs by instrumentation, and exposure to contaminated solutions. percutaneous inoculation, ingestion, or inhalation from environment, contact with infected animals and even Melioidosis laboratory acquired infections have been reported.12 Few It is a disease of human and animals caused by B. other strains like B. gladioli and B. pickettii have also been pseudomallei. Every year approximately 1,65,000 reported to cause nosocomial infections and multidrug people are infected by melioidosis, resulting in death of resistant outbreaks in certain communities and hospitals approximately 89,000 infected patients.17 The incubation posing an emerging threat to the society. However, little is period for the disease has been recorded to be as less 18 known about the epidemiology of these particular species. as 1 day to up to a period of 62 years. Because of its prolonged incubation period the disease has also been Clinical Manifestations referred as “Vietnamese time bomb.”19 One or more risk factors for the disease are found in up to 80% patients. BCC Infection in Cystic Fibrosis Well-known risk factors for melioidosis include diabetes Owing to increased life expectancy in patients with CF, mellitus, heavy alcohol use, chronic pulmonary disease, BCC has emerged as a major cause of morbidity and chronic renal disease, glucocorticoid therapy and cancer.20 mortality. There is chronic colonization of the major The spectrum of clinical manifestations is greatly varied airways with BCC in these patients and it may persist for ranging for acute fulminant septic illness to a chronic months to years. Up to 20% of the infected patients rapidly infection that may be confused with tuberculosis or

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Fig. 1: Chest X-ray showing a right lower lobe pneumonia in patient Fig. 2: Pus draining from a localized abscess in a diabetic patient with BCC infection with melioidosis

malignancy for which it has been nicknamed as “The septicemic form of glanders has been as high as 95% Great Imitator.”21 The disease can manifest as an acute without treatment and about 40–50% with treatment.24 infection seen in 85% of the patients as pneumonia, sepsis or localized abscess (Fig. 2); as chronic infection seen Others in 10% of the affected group, where it mimics symptoms Other members of the Burkholderia species like B. gladioli of tuberculosis; and as a latent infection in 5% of the and B. pickettii have been rarely found to cause infections patients who are immunocompetent. The most common in CF patients and hospital outbreaks. However, a little is presentation is pneumonia (Fig. 3), while others are known regarding the clinical features and etiopathogenesis genitourinary infection, skin infection, overwhelming of these two species. sepsis with abscesses disseminated in multiple internal organs (Fig. 4), septic arthritis (Fig. 5), and osteomyelitis. Mortality rates for melioidosis are approximately 40% Diagnosis in Northeast Thailand (35% in children) and 14% in Identifying Burkholderia species has been a tedious task Australia.22 because of poor laboratory proficiency throughout the world. A combination of selective media, biochemical Glanders analysis along with commercial kits, is being routinely Glanders is a highly contagious and fatal disease of the used for species identification. For identifying BCC, three equine. It is caused by the organism B. mallei.23 In India, selective media are used; the P. cepacia agar (PCA), the it is a notifiable disease and more than 50% cases of oxidation-fermentation polymyxin bacitracin lactose agar equine glanders have been reported from Uttar Pradesh.24 (OFPBL), and the B. cepacia selective agar (BCSA). BCSA is The incubation period for the acute form of disease is the most recent and preferred selective media used. Apart 1–14 days, while for the chronic form, the incubation from BCC, other members of the species like B. gladioli, period may be to 12 weeks. Clinically, it may manifest as Ralstonia spp., and Pandoraea spp. can also be grown in a local infection with nodules and lymphadenitis when BCSA. Similarly, out of various culture medias used for transmitted by skin inoculation. Pneumonic forms are identification of B. pseudomallei, the Ashdown’s selective usually transmitted through inhalational route. Patient agar (containing gentamicin), is the most commonly used. may develop septicemia with shock when organism The characteristic “safety pin” appearance on Gram’s disseminates from the skin or lungs causing significant staining in a histopathological specimen also helps in mortality. The mortality of pulmonary form and the identification of B. pseudomallei. Use of automated

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Fig. 3: HRCT thorax revealing multiple bilateral opacity in a patient suffering from melioidosis

identification systems like API 20, Phoenix, Microscan, basis of morphology and serologic tests is also a tedious and Vitek 2 to identify BCC complex is also on the rise task. Molecular identification has been a breakthrough nowadays, but the identification is not trustworthy as recently where identification is performed by DNA many of the species of NFGNB are misidentified as BCC. based polymerase chain reaction, which identifies the Distinguishing B. pseudomallei from B. mallei on the differences in sequence of 16S rRNA gene or recA gene,

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Fig. 4: CT abdomen showing multiple abscesses in liver and spleen Fig. 5: Septic arthritis involving knee in a patient with melioidosis in a immunocompromised patient suffering from melioidosis (Source: Patro S, Panda SS, Mishra D, et al. Burkholderia infections in diabetic patients emerging as a challenge for physicians: a case series. J Clin Diagn Res. 2019;13:OD04-07.)

that help in distinguishing the species. Other methods of infection and prevent relapse. Alternative eradication molecular identification like MALDI-TOF MS, multilocus therapies include doxycycline and co-amoxiclav but both restriction typing, pulsed field-gel electrophoresis, and therapies have a higher rate of relapse.21 BOX-PCR have been equally found effective in identifying species.25 Burkholderia mallei Infections This organism causes human infection rarely, so there Management is limited information available regarding choice of antibiotics. Because of its similarities with B. pseudomallei, Burkholderia cepacia Infections it is postulated that the drug susceptibility would be This organism is intrinsically resistant to many of the same. Susceptibility to macrolides, azithromycin, and antimicrobial agents, which pose the greatest challenge clarithromycin have also been reported.16 in its management. The BCC isolates from CF patients have shown to be substantially more resistant. Therefore, Conclusion combination drug therapy for serious infections has been suggested. Antimicrobials that are most effective and Most of the Burkholderia species infections are hospital acquired considered first line are Trimethoprim-sulfamethoxazole and potentially pathogenic in individuals with impaired host (TMP-SMX), Meropenem, and Doxycycline. Some strains defense, which can lead to septicemia and acute respiratory distress syndrome (ARDS) with requirement of ventilator and are also susceptible to third-generation ureidopenicillins, 16 perfusion support if not intervened at the earliest. Treatment of advanced cephalosporins, and fluoroquinolones. this infection is really a challenge to physicians as patient needs long-term antibiotic therapy and recurrence of infection is very Burkholderia pseudomallei Infections common even after prolonged treatment. As these infections Treatment is divided in two phases: the “induction carry a very grave prognosis, hence, high risk of suspicion is phase” for 2 weeks with intravenous ceftazidime or a required in all cases of septicemia and ARDS particularly with carbapenem (either Meropenem or imipenem), and impaired host defense. Prompt management of the infection and the underlying conditions will definitely reduce the the “eradication phase” with 12 weeks of oral antibiotics mortality and morbidity to a great extent. such as trimethoprim-sulfamethoxazole to eradicate the

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References 12. Wisplinghoff H. Pseudomonas spp., Acinetobacter spp. and miscellaneous Gram-negative bacilli. Infectious Diseases. Elsevier; . 1 Burkholder WH. Sour skin, a bacterial rot of onion bulbs. 2017. pp. 1579-99. Phytopathology. 1950;40(1):115-7. 13. Coenye T, LiPuma JJ. Molecular epidemiology of Burkholderia . 2 Coenye T, Vandamme P. Diversity and significance of Burkholderia species. Front Biosci. 2003;8:e55-67. species occupying diverse ecological niches. Environ Microbiol. 14. Hauser N, Orsini J. Cepacia syndrome in a non-cystic fibrosis 2003;5(9):719-29. patient. Case Rep Infect Dis. 2015;2015:537627. 3. Abe K, D’Angelo MT, Sunenshine R, et al. Outbreak of Burkholderia 15. Snell GI, de Hoyos A, Krajden M, et al. Pseudomonas cepacia in lung cepacia bloodstream infection at an outpatient hematology and transplant recipients with cystic fibrosis. Chest. 1993;103(2):466-71. oncology practice. Infect Control Hosp Epidemiol. 2007;28(11): 16. Fauci AS, Jameson JL, Kasper DL, et al (Eds). Harrison’s Principles 1311-3. of Internal Medicine, 20th edition. New York: McGraw Hill, Health 4. Patro S, Panda SS, Mishra D, et al. Burkholderia infections in diabetic Professions Division; 2018. pp. 114-22. patients emerging as a challenge for physicians: a case series. J Clin 17. Wiersinga WJ, Virk HS, Torres AG, et al. Melioidosis. Nat Rev Dis Diagn Res. 2019;13:OD04-07. Primers. 2018;4:17107. . 5 Palleroni NJ, Kunisawa R, Contopoulou R, et al. Nucleic acid 18. Ngauy V, Lemeshev Y, Sadkowski L, et al. Cutaneous melioidosis in homologies in the genus Pseudomonas. Int J Syst Evol Microbiol. a man who was taken as a prisoner of war by the Japanese during 1973;23(4):333-9. World War II. J Clin Microbiol. 2005;43(2):970-2. 6. Achouak W, Christen R, Barakat M, et al. Burkholderia caribensis sp. 19. Rathor N, Khillan V. “Vietnamese time bomb” waiting to explode; nov., an exopolysaccharide-producing bacterium isolated from Burkholderia pseudomallei, retributing the “rare” tag. An update. vertisol microaggregates in Martinique. Int J Syst Evol Microbiol. Indian Journal of Medical Specialities. 2016;7(3):116-24. 1999;49(2):787-94. 20. Raja NS, Scarsbrook C. Burkholderia pseudomallei causing bone and . 7 Vandamme P, Holmes B, Vancanneyt M, et al. Occurrence of joint infections: a clinical update. Infect Dis Ther. 2016;5(1):17-29. multiple genomovars of Burkholderia cepacia in cystic fibrosis 21. Singh M, Mahmood M. Melioidosis: the great mimicker. J patients and proposal of Burkholderia multivorans sp. nov. Int J Syst Community Hosp Intern Med Perspect. 2017;7(4):245-7. Evol Microbiol. 1997;47(4):1188-200. 22. Currie BJ, Ward L, Cheng AC. The epidemiology and clinical . 8 Baldwin A, Mahenthiralingam E, Drevinek P, et al. Environmental spectrum of melioidosis: 540 cases from the 20 year Darwin Burkholderia cepacia complex isolates from human infections. prospective study. PLoS Negl Trop Dis. 2010;4(11):e900. Emerg Infect Dis. 2007;13(3):458. 23. Van Zandt KE, Greer MT, Gelhaus HC. Glanders: an overview of . 9 Lipuma JJ, Spilker T, Gill LH, et al. Disproportionate distribution of infection in humans. Orphanet J Rare Dis. 2013;8(1):1-7. Burkholderia cepacia complex species and transmissibility markers 24. Malik P, Singha H, Goyal SK, et al. Incidence of Burkholderia mallei in cystic fibrosis. Am J Respir Crit Care Med. 2001;164(1):92-6. infection among indigenous equines in India. Vet Rec Open. 10. Chaowagul W, White NJ, Dance DA, et al. Melioidosis: a major cause 2015;2(2):e000129. of community-acquired septicemia in northeastern Thailand. J 25. Karger A, Stock R, Ziller M, et al. Rapid identification of Burkholderia Infect Dis. 1989;159(5):890-9. mallei and Burkholderia pseudomallei by intact cell Matrix-assisted 11. Wheelis M. First shots fired in biological warfare. Nature. Laser Desorption/Ionisation mass spectrometric typing. BMC 1998;395(6699):213. Microbiol. 2012;12:229.

MU-172.indd 1126 29-01-2021 15:05:42 CHAPTER Managing Dermatophytosis (Tinea Infections) in 173 Today’s Scenario

Basavana Gowdappa Hathur, Garehatty Rudrappa Kanthraj

Abstract Dermatophytosis is common fungal infection in human population. These keratinophilic fungi are restricted to the stratum corneum. The frequent strain causing infection earlier was Trichophyton rubrum; but at present, Trichophyton mentagrophyte is found to be common pathogen. Dermatophytosis requires prolonged treatment. Change in the fungal species, resistance, and steroid abuse leading to reinfection make the condition refractory to treatment. Details of treatment taken and family history are important. Appropriate combination of oral and topical antifungal agents and counseling for better adherence to treatment are needed in resistant and steroid misuse cases.

Introduction like high humidity, hygienic practice of the individual, and risk proportion of individuals to acquire infection, “Ringworm” infection is frequently used terminology for can change from region to region. The dermatophytosis dermatophytosis. This infection basically involves the can have seasonal influence, with higher incidence in keratinized tissue of the superficial layers of skin. There summer and lower in other seasons. Nearly quarter of are three genera among dermatophytes: Epidermophyton, Microsporum, and Trichophyton. These fungi are global population is expected to have dermatophytosis keratinophilic and have capacity to invade the keratinous as per WHO estimates. There can be 30–70% of general 2 tissue of living animals. The involvement of epidermis, population who are asymptomatic carriers. especially stratum corneum and tissue with higher keratin Trichophyton rubrum, Trichophyton mentagrophytes, contents like hair and nails is common. These organisms Microsporum canis and Trichophyton tonsurans are unable to penetrate deeper layers of skin or organs in are frequently seen pathogens to cause cutaneous immune-competent individuals and commonly confine fungal infection. Tinea capitis is commonly caused by to superficial non-living cornified layers. The clinical Trichophyton tonsurans. Tinea pedis, Tinea unguium, 2 manifestations are basically dependent on response of the Tinea corporis, and Tinea cruris are commonly caused by infected individual to dermatophytosis, which can vary T. rubrum. between milder to significant clinical expression. These These cutaneous fungal infections can produce are mainly caused by reaction of host to the metabolic significant impact on quality of life. They can be products of the organism, degree of virulence, anatomic responsible for lot of social embarrassment, psychosocial location of the infection, and prevailing environmental discomfort, and impact on their work environment and factors.1 hamper efficiency. The best way to reduce morbidity and There can be lot of geographical variation in incidence restrict transmission is by diagnosing early and providing and prevalence of these fungal infections. Several factors, proper health education for prevention and adherence

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to treatment. Therapy can be protracted and produce TABLE 1 The Mechanism of action of antifungal drugs financial concerns. Disrupted therapy can be one of the important causes for relapses. There can be frustrations Class Mechanism of action among treating clinician due to inadequate therapeutic Alkylamine Inhibition of squalene epoxide response and relapse. e.g., Terbinafine Azoles Inhibition of 14–α-demethylase Changing Scenario of Dermatophytes Griseofulvin Disruption of mitotic spindle Amphotericin B Bind to fungal cell membrane ergosterol There is an epidemiological transition of dermatophytosis Flucytosine DNA–RNA inhibitors in India. T. rubrum was found to be common pathogen in the past by many observers in India; however, at present it is significantly less prevalent. T. mentagrophyte is presently TABLE 2 Common topical antifungal creams used found to be frequent when compared to past.3 Antifungal class Formulations with concentrations Antifungal Drugs: Mode of Action Azoles-Imidazoles zz Clotrimazole 1% cream zz Ketoconazole 2% cream See Table 1. zz Miconazole 2% cream zz Bifonazole 1% cream zz Oxiconazole 1% ream Treatment of Dermatophytosis zz Sertaconazole 2% cream zz Luliconazole 1% cream 4 Common topical antifungal cream used (Table 2). zz Eberconazole 1% cream Duration of treatment is given for 4–6 weeks or longer, zz Fenticonazole 2% cream depending on clinical severity and therapeutic response Triazoles Fluconazole 0.5% gel (Modified and reproduced with permission from Poojary Alkyl amine Terbinafine 1% cream 4 SA). Benzylamine Butenafine 1% cream Common clinical situations for use of topical Morpholine Amorolfine 0.25% cream, 5% nail laquer preparations: Hydroxypyridinones Ciclopirox 1% cream, naillaquer „„ Infections during conception and first trimester Source: Modified and reproduced with permission from reference 4. „„ Patients with renal, hepatic, and cardiovascular diseases „„ Patients who are taking compelling medications for Advantages of topical versus oral antifungals: comorbidities with potential interaction „„ Insignificant side effects Common guidelines for improved therapeutic „„ Less chances of interaction with other drugs outcomes of using topical preparations: „„ Can have better psychological effect with pharmaco­ „„ Medication should be applied over the lesion and economy surrounding skin, starting from outer aspect Disadvantages of topical preparations: „„ Choice of formulation can be variable, based on the „„ Difficult to use in extensive infection region of the disease: „„ Poor response due to inadequate quantity of —— Liquid preparations: Web spaces, axilla, external application genitalia, wet-lesions, and larger area of „„ Inability to apply in difficult to reach areas, which leave involvement a residual focus of infection4 —— Creams: Dry lesions, lesions with prurigo —— Ointments: Hyperkeratotic lesions —— Gels: Over the facial region Adverse Effects of Topical Antifungals —— Nail lacquers: Subungual lesions Topical applications are well tolerated with few adverse —— Shampoos: As additional component in tinea effects like pruritus, burning sensation, irritation, capitis erythema, maceration, and fissuring.4

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TABLE 3 Common oral antifungals used

Condition Drug Dosage and duration Tinea corporis/cruris zz Terbinafine zz 250 mg/day od, 3–6 mg/kg for 2–3 weeks zz Itraconazole zz 200 mg/day for 1–2 weeks zz Fluconazole zz 150–300 mg/week for 3–4 weeks zz Griseofulvin (microsize) (ultra-micro size) zz 500 mg/day (10–20 mg/kg) for 2–4 weeks zz 300–375 mg/day (5–10 mg/kg) Tinea pedis zz Terbinafine zz 250 mg od for 1–2 weeks zz Itraconazole zz 100–200 mg/day for 2–4 weeks zz Fluconazole zz 150 mg/week for 1 month zz Griseofulvin zz 750–1000 mg/day 4–8 weeks zz 660–750 mg/day (Modified and reproduced with permission from Reference 5.)

Common oral antifungals used are summarized in inhibitors can cause several drug interactions and Table 3. terbinafine is safe in elderly and can be the drug of first Clinical situation where the systemic antifungals are choice. Topical terbinafine, ketoconazole, or clotrimazole required: cream is preferred. „„ Involvement of scalp (Tinea capitis) Fluconazole is the safest oral antifungal in hepatic „„ Involvement of the nails and renal disorders. Topical terbinafine, ketoconazole, or „„ Fungal infection at many areas of the body clotrimazole cream is preferred in hepatorenal disorders. „„ Tinea corporis with extensive involvement The following are the challenges encountered in the 5 „„ Tinea pedis with extensive involvement treatment of dermatophytosis: „„ Resistance Adverse Effects of Oral Antifungals „„ Recurrence „„ Reinfection Gastrointestinal disturbances, altered LFT, headache, „„ Misuse of topical steroids pruritus, and cutaneous allergic reactions are common. „„ Associated comorbidities Erythema multiforme and toxic epidermal necrolysis „„ Immunosuppression can occur. Lupus erythematosus and psoriasis can be exacerbated. Antifungal Resistance Drug Interactions of Oral Antifungals Antifungal resistance can be either microbiological resistance or clinical resistance. Resistance as assessed Terbinafine is predominantly metabolized by CYP2D6. by in vitro susceptibility testing shows resistance, with Caution should be exercised while prescribing tricyclic exceeding of MIC from susceptibility breakpoint. The antidepressants, SSRI, beta-blockers antiarrhythmics, resistance, which occurs naturally, is primary where MAO inhibitors, warfarin, cyclosporine, and rifampin. the organism is not exposed to the drug previously. The These are common drug interactions of oral antifungal genetic mutation basically contributes to secondary agents. resistance and the organism would have been susceptible to the same agent previously. Antifungals in Elderly Several factors can contribute to inadequate clinical The presence of comorbidities and higher drug response, it could be due to inadequate dose, improper interactions warrants caution for antifungals for the adherence to therapy or altered genetic profile of elderly. Fluconazole and itraconazole being CYP3A4 pathogen, or the therapeutic agent selected may be

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wrong. The resistance to griseofulvin and terbinafine tight-fitting clothes, and sharing of community bath and in some dermatophytes have been reported in India. sports facilities. The clinical response and susceptibility assessment may not correlate; hence, it is not appropriate to use Future Directions for Prevention of the term, “resistant” in the absence of these definitive Refractory Dermatophytosis criteria for these fungal infections. Assessment of in-vitro The primary factor for emergence of antifungal resistance susceptibility to terbinafine, fluconazole, and griseofulvin appears to be inadequate dose and improper combination. as reported in many studies does not imply that there There is need of clear guidelines for dose recommendation is an absolute resistance, the clinicians should think of for prevention and treatment. using better dosage or prolonged treatment for adequate Ghannoum and Rice7 suggested for intense clinical response. The antifungal drug susceptibility is said to be correlation with appropriate medication combination and different in Indians, hence there is need to establish dose acceptable dosage by using the pk/pd data and surveillance determination and MIC breakpoint guidelines by the inputs. Early diagnosis with correct combination will help Clinical Laboratory Standards Institute (CLSI). in reducing resistance and refractoriness. Measures improve hand hygiene: Hand wash; clipping Steroid Abuse in Tinea of nail; regular bathing, keeping the skin dry, use of proper Steroid modified tinea is a common problem in India. shoes, cotton socks, and absorbent powder; avoidance Permutation and combination of various antifungals, of sharing of bathing facilities and cloths; avoidance of antibacterials, and topical potent corticosteroids are walking barefoot in public bathroom are important in used. Nearly half of the sales of these combinations in preventing spread.8 India are due to self-medication or advice by unqualified Using appropriate combination of drugs will increase persons. The combination of clobetasol propionate, the fungicidal effect and increase the spectrum of activity ornidazole, ofloxacin, and terbinafine are frequently and reduce refractoriness. Choose a combination of oral used in India. Irrational and non-supervised use has and topical antifungal with different mechanism of action aggravated the problem. Long time and intermittent for better clinical outcome. use result in erythema, telangiectasia, and atrophy. The Antifungal drugs in the pipeline that are active against clinical picture variable due to altered T-cell mediated azole-resistant isolates, like cationic peptide histatin immunity suppression. Ineffective elimination of the will be important for revised treatment strategies. The dermatophyte results in chronic, wide-spread, and ill- combined use of azoles and cytokines will be useful in defined lesions. Constant itching and scratching result in treatment of fungal infections in immune-compromised lichenification. Improper central clearing due to topical individuals. steroid abuse results in various bizarre shapes mimicking Tinea pseudoimbricata. Supervised short duration of Conclusion

topical steroid is required to treat lichenification followed zz Cutaneous fungal infections are very common in by antifungal treatment. Prolonged treatment needs humans. Dermatophytes have higher affinity to stratum counseling for adherence to the treatment.6 corneum. The common strain is T. mentagrophytes among dermatophytes. Tinea corporis and cruris require 3–4 weeks Recurrence of treatment. zz Fingernail requires 6–8 weeks; however, toenail requires There is lack of uniformly acceptable definition of 10–12 weeks of treatment. “recurrent dermatophytosis.” Whenever there is a protracted zz Patients with renal, liver, and cardiovascular diseases are course with variable degree of persistence of lesions, these treated with topical antifungal. patients contribute for easy spread of infection to family zz Resistance, recurrences, reinfection, topical steroid misuse, members and other closely associated people. Common and associated comorbidities pose a clinical challenge in contributing factors are overcrowding, living together antifungal treatment. in congested accommodation, the use of tight footwear, Contd...

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Contd... . 2 Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for superficial mycotic infections of the skin: tinea-corporis, tinea- zz Steroid modified tinea in India is a result of topical cruris, tinea-faciei, tinea-manuum, and tinea-pedis. J Am Acad antifungal used in combination with potent topical steroids Dermatol. 1996;34(2.1):282-6. and antibacterial that account for about 50% of the sales of . 3 Verma S, Madhu R. The great Indian epidemic of superficial all topical steroids in India. dermatophytosis: an appraisal. Indian J Dermatol. 2017;62(3):227-36. zz Careful history taking-treatment history, combination of . 4 Poojary SA. Topical antifungals: a review and their role in current oral and topical antifungal with different molecules that management of dermatophytoses. Clin Dermatol Rev. 2017;1(3):24. have varied mechanism of action and counseling is needed . 5 Sahoo AK, Mahajan R. Management of tineacorporis, tineacruris, in resistance and topical steroid misuse cases. and tineapedis: a comprehensive review. Indian Dermatol Online J. 2016;7(2):77-86. zz Drug interactions must be considered before starting any . 6 Verma SB. Sales, status, prescriptions and regulatory problems oral antifungals. with topical steroids in India. Indian J Dermatol Venereol Leprol. 2014;80:201-3. . 7 Ghannoum MA, Rice LB. Antifungal agents: mode of action, References mechanism of resistance, and correlation of these mechanisms 1. Sharma R, Adhikari L, Sharma RL, et al. Recurrent dermatophytosis: a with bacterial resistance. Clin Microbiol Rev. 1999:12(4);501-17. rising problem in Sikkim, a Himalayan state of India. Indian J Pathol . 8 Pai V, Ganavalli A, Kikkeri NN, et al. Antifungal resistance in Microbiol. 2017;60(4):541-5. dermatology. Indian J dermatol. 2018;63(5):361-8.

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174 Rickettsial Infection

Vasantha Kamath, Shreyashi Ganguly, P Siva Karthik Reddy

Abstract Rickettsial infections are important public health problems and are often underdiagnosed or misdiagnosed leading to the burden of morbidity and mortality due to nonspecific symptoms and signs and absence of specific diagnostic tests. The present review addresses the epidemiology, clinical features, diagnosis, complications, and management of these infections, primarily for a practicing clinician.

Introduction grade continuous fever, centripetal/centrifugal rash, generalized lymphadenopathy, decreased platelets, and The rickettsioses represent one of the important causes the pathognomonic eschar (tachè noire) which is rarely of febrile thrombocytopenia worldwide. Rickettsial seen in our setup. However, atypical presentations are infections which were initially seen more often had also more prevalent in hyperendemic areas.3 Clinical reduced in incidence with extensive use of pesticides presentation along with positive Weil Felix test is employed to control vectors. Tetracycline was one of the most to make the diagnosis of rickettsiosis.4 commonly used antibiotics which also contributed to reduction of prevalence of rickettsial infections. However, the indiscriminate use of tetracycline has declined due Structure and Genome 1 to adoption of better antibiotic policies. Additionally, Rickettsia is small, Gram-negative coccobacillary form the urbanization of rural areas has exposed more of the adapted to obligatory intracellular parasitism and population to potential sources of infection. These two transmitted by arthropod vector (lice, flees, ticks, and factors have coincided with the re-emergence of this 1 mites) found in their alimentary canal. In vertebrates deadly scourge. especially humans they infect vascular endothelium and These diseases can be incapacitating and difficult reticuloendothelial cells.5 Rickettsiae are not evident on to diagnose in resource-poor settings. Potential cases blood smear and do not stain with most of the conventional are often under-recognized or under-tested. Adding to 3 stains; however, it stains red with Giemsa stain. Rickettsial the burden of morbidity and mortality is the dearth of genome is 1–1.5 Mb and is a single circular genome. adequate laboratory testing facilities and uniformity of reporting systems.2 Rickettsioses present with non-specific signs. The Rickettsiaceae Family However, certain clinical features are indicative when Family Rickettsiaceae is divided based on lipopoly­ present in a constellation, such as the presence of high- saccharide group antigen into four genera (Flowchart 1).

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Flowchart 1: Classification of rickettsial infections

Vectors Transmission is by arthropod vectors like lice, fleas, ticks, and mites.

Distribution The distribution is dependent on the arthropod host/ vector. Tick vector dependent infections have limited geographic spread (except Antarctica).1,2

Risk Factors People staying near mountains, bushes, and equatorial rain forests are at risk. Improper hygiene and rearing of domestic animals are also risk factors.3 Fig. 1: Rickettsial rash Pathogenesis Endothelial cells are primary target (exception Rickettsia (abdominopelvic, para-aortic, porta hepatis, splenic akari). They cause damage to the cell causing cellular 6,7 hilum), and hepatosplenomegaly. detachment. The cells in circulation when lodged in distal capillaries become the source of infection. Through The rash: Though considered as characteristic feature antibody, mediated opsonization rickettsia can enter of rickettsioses is not seen in all patients. It occurs on phagocytic cell.3 the third or fifth day of illness. It may be typical with macules, papules, hemorrhage, or petechiae or atypical Clinical Features asymmetrical localized to small area (Fig. 1). It may be centripetal or centrifugal in distribution mainly seen over The incubation period varies 2–21 days. Signs and symptoms the soles of the feet and palms of the hand.3,8 are non specific. Fever is the most common presentation which starts abruptly and is of high grade in association with Eschar: It is vesicular lesion at the site of inoculation which headache, muscle ache, apathy, drowsiness, photophobia, ulcerates, heals with development of black necrotic scar conjunctival suffusion, generalized lymphadenopathy associated with regional lymphadenopathy. Necrotic

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Neurological complications of ricketsioses are encephalitis, aseptic meningitis, meningoencephalitis; respiratory symptoms like cough and breathlessness associated with ARDS and pneumonia and non- cardiogenic pulmonary edema (30–60%), gastrointestinal manifestations presenting as acute gastroenteritis, severe pain abdomen often mistaken for surgical abdomen; transaminitis with acute hepatitis and hepatic encephalopathy, coagulation factor consumption results in a DIC-like syndrome.7 Differential diagnosis of aseptic meningitis should include rickettsial meningoencephalitis in endemic areas, especially when associated with altered renal or hepatic functions. Acute kidney injury is associated with poor 3 Fig. 2: A classical eschar prognosis. Retinal vasculitis is commonly seen amongst females. It is asymptomatic in the early stage, resolves by 6 months. eschar (Fig. 2) is seen in belt area, in groin, under the arms, The prognosis is favorable.3 sometimes over the neck. Even though it is the single most Without medications uncomplicated infection might important clue for the diagnosis it is recognized in less recover within 14 days. Untreated cases carry a mortality than 50% even by an experienced physician. Sometimes rate of 30%. Persistent subclinical infection in convalescent multiple eschars are seen under the trouser belt. Scrub patients occurs with Rickettsia prowazekii, which later typhus patients with virulent strains have lower incidence presents as recrudescent typhus or Brill-Zinsser disease.2,9 of rash/eschar, and hence severity of clinical features People travelling from disease endemic region might depend on serotype and genotype of rickettsia. present with symptoms within few days of return. Since In India, three common groups of infections are seen the incubation period for most rickettsial infections is the spotted fever group (e.g., R. akari), the typhus group from 2–21 days, symptoms which begins 20 days after (e.g., R. typhi), scrub typhus (Orientia tsutsugamushi). The travel from a disease-endemic area has less probability to 8 significant clinical differences between them have been be a rickettsial infection. studied by the author’s team.9,10 Scrub typhus was more likely to present with fever Investigations 7–14 days (p=0.03); splenomegaly (p=0.023), and eschar Early stages—lymphopenia; late stages—lymphocytosis (p=0.014) were significant examination findings; in (30%), Elevated ESR, decreased platelet count in less than the laboratory, it presents with increased SGOT/SGPT 50% of cases. (p=0.024), and decreased albumin (p=0.021). Spotted Later—Deranged liver function test (50%): Increased fever group had a preponderance toward fever less serum bilirubin, increased ALT, AST (75–95%), reduction than 7 days (p=0.043), vomiting (p=0.03), and joint pain in albumin less than 3 gm% (seen in significant number (p=0.049). Macular rash (p=0.04) was observed clinically. of patients); reduced sodium, increased blood urea, and Pleural effusion (p=0.021) was a significant complication. serum creatinine. Typhus group had fever more than 14 days (p=0.04), Chest X-ray: Pneumonitis, bilateral infiltrates, pleural associated with cough (p=0.019), and abdominal pain effusion, and ultrasound abdomen: Hepatosplenomegaly.11 (p=0.039). Hepatomegaly (p=0.045) was a significant clinical finding.10 Atypical presentation that may be seen in hyperendemic Diagnosis areas are: acute abdomen without fever, nausea, vomiting, Early stages: It is challenging to diagnose these infections diarrhea, and constipation. and differentiate them from other infections like dengue,

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malaria. The clinical manifestations of most rickettsioses results. Immunoglobulin M rises at the end of first week; present as a continuous spectrum. In the absence of Immunoglobulin G rises at the end of second week. definite pathognomonic signs, there are signs and symptoms highly suggestive of the etiology. However, Immunohistologic Examination not all cases present with the set of typical clinical The only diagnostic test proved useful during acute illness manifestations that aid in prompt recognition. As such the is immunohistologic examination from cutaneous biopsy clinical acumen and awareness of the treating physician sample of a rash or biopsy of a lymph node. It is 70% has a great role in the diagnosis and management of these sensitive, 100% specific. However, high expertise is needed cases. In resource poor country, fever with rash, fever with to interpret biopsy result.3,11 thrombocytopenia and rash Weil Felix test clinches the 11 diagnosis. Polymerase Chain Reaction It is species specific and is positive in initial 7 days. It can When to Suspect Rickettsial Infection? be done on whole blood, eschar, or skin biopsy. It has a Any patient presenting with fever and rash, fever and specificity of 100% for both PCR and Rt-PCR and sensitivity eschar, aseptic meningitis, acute renal failure with eschar, of 22–36% for PCR and 45–82% for Rt-PCR. Tissue sample increased vasculitis should be suspected of having shows higher sensitivity compared to blood sample. rickettsial infection. Culture Weil-Felix Test Organism is grown on tissue culture Vero cell of kidney, This test is easily available, cheap, and easy to perform. egg yolk sac and isolation needs biosafety level III labs. The results are available on the same day. The sensitivity However, culture is unnecessary, laborious and hazardous is 46%, specificity is 100%, is positive in second week. OX2, to lab personnel. Median time for reporting is 27 days. OX19, and OXK strains of agglutinins of proteus bacteria 3,8,11 are used in the test. Results must be interpreted in Treatment the correct clinical context (Table 1). Value of testing If cases are left untreated fatality may go up to 30%.1,3 two sequential serum or plasma samples together with When diagnosed properly it can be treated easily, but the fourfold rise in antibody level is more important in difficulty lies in diagnosing rickettsial infection during confirming acute infection.3,8,11 initial phase of the disease when antibiotic use is very effective.12 Indirect Immunofluorescence Assay/ Doxycycline is the treatment of choice. Dose 100 mg Immunoperoxidase Assay two times a day should be used for 7–10 days. Within It is the gold standard investigation. Sensitivity is 89–100%, 24–48 hours after initiation of antibiotic, patient improves specificity is 100%, but major constraints being, the test is drastically. If patient fails to respond within 48 hours, not easily available, costly, and takes more than 7 days for it is unlikely to be Rickettsial infection.12 Extremely sick patients (especially with MODS and ARDS) may require 10–14 days to respond to treatment. Relapse is usually TABLE 1 Interpretation of Weil-Felix test seen if treatment is discontinued as soon as fever subsides. Diseases Weil-Felix Discoloration of teeth is more common in children and 13 OX-19 OX-2 OX-K depends on duration of treatment, other side effects are Rocky mountain spotted fever + + – hypoplasia of the enamel, depression of skeletal growth, and limb hypoplasia. As such, doxycycline should not be Rickettsial-pox – – – used in children less than 8 years because of these above Epidemic typhus + – – side effects. In pregnant women due to the adverse effects Endemic typhus + – – on the skeletal growth of fetus. Azithromycin 500 mg once Scrub typhus – – + daily is used instead in this setting.7

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If patients respond poorly to doxycycline or drug resistant rate up to 30%. When diagnosed properly it is often easily serotypes: combination of doxycycline with rifampicin for treated. Greatest challenge is difficult diagnostic dilemma 6–8 days or azithromycin with rifampicin (600 mg once a day) posed by these infections early in clinical course when to be used. Rifampicin should always be used in combination antibiotic therapy is most effective; hence, physicians and as it leads to resistance when used alone. In India, rifampicin pediatricians have to include rickettsial infection in differential is avoided due to the prevalence of tuberculosis. diagnosis of acute febrile thrombocytopenia. Treatment in pregnancy: Chloramphenicol is also an alternative drug and can be recommended for use in References pregnancy in dose 500 mg four times a day for 7–14 days but has to be avoided in last trimester due to fear . 1 Raoult D, Roux V. Rickettsioses as paradigms of new or emerging infectious diseases. Clin Microbiol Rev. 1997;10(4):694-719. of bone marrow suppression and gray baby syndrome. . 2 Kelly DJ, Richards A, Temenak J, et al. The past and present threat Azithromycin is safer alternative in pregnancy. A macrolide, of rickettsial disease to military medicine and international public Josamycin, has been used with success in spotted fever health. Clin Infect Dis. 2002;34(4):145-69. group in pregnancy in a dose of 3 gm/day orally for 5 days. 3. Kamath V, Ganguly S, Bhatia JK, et al. Rickettsial infections: past and Doxycycline can be used in late pregnancy. present perspectives. APIK J Int Med. 2020;8:4-10. . 4 Rathi N, Rathi A. Rickettsial infections: Indian perspective. Indian Vaccine Pediatr. 2010;47(2):157-64. . 5 Walker DH, Yu X-J. Progress in rickettsial genome analysis from No vaccine is available for Rickettsial infection. An ideal pioneering of rickettsia prowazekii to the recent rickettsia typhi. vaccine should give protection to all biogroups in order to Ann N Y Acad Sci. 2005;1063:13-25. give acceptable level of protection. This complexity continues 6. Merhej V, Raoult D. Rickettsial evolution in the light of comparative to hamper efforts to produce effective viable vaccine due to genomics. Biol Rev Camb Philos Soc. 2011;86(2):379-405. . 7 Sirisanthana V, Puthanakit T, Sirisanthana T, et al. Epidemiologic, enormous antigenic variations among the biogroups. clinical and laboratory features of scrub typhus in thirty Thai children. Pediatr Infect Dis J. 2003;22(4):341-5. Recent Developments . 8 Walker DH, Raoult D. Rickettsia rickettsii and other spotted Rickettsiae have specific regions of oompA and oompB fever group rickettsiae. In: Mandell GL, Bennet JE, Doalin R (Eds). surface proteins and measures to detect antibodies Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone; 2000. pp. 2035-42. against them, might prove beneficial in future treatment 9. Faccini-Martínez ÁA, García-Álvarez L, Hidalgo M, et al. Syndromic 3 of rickettsiae. classification of rickettsioses: an approach for clinical practice. Int J Infect Dis. 2014;28:126-39. Prevention 10. Kamath V, Bindu BH, Ganguly S, et al. A study of the comparative Preventing exposure to a vector infested habitat, wearing clinical profiles of scrub typhus, spotted fever group, and typhus group rickettsial infections at a rural tertiary care hospital. APIK J Int closed-toed shoes, long pants, long sleeved clothes, Med. 2020. topical application of insect repellents, protected pets may 11. Luce-Fedrow A, Mullins K, Kostik AP, et al. Strategies for detecting help in prevention. rickettsiae and diagnosing rickettsial diseases. Future Microbiol. 2015;10(4):537-64. 12. Van Eekeren LE, de Vries SG, Wagenaar JFP, et al. Under-diagnosis Conclusion of rickettsial disease in clinical practice: a systematic review. Travel Rickettsial infections are some of the covert re-emerging Medicine and Infectious Disease. 2018;26:7-15. Available from infections of present times generally incapacitating and https://doi.org/10.1016/j.tmaid.2018.02.006 notoriously difficult to diagnose. Untreated cases have fatality 13. Lochary ME, Lockhart PB, Williams WT, et al. Doxycycline and staining of permanent teeth. Pediatr Infect Dis J. 1998;17(5):429-31.

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175 Adult Vaccination

Nirupam Prakash, Hemant Mittra, Jeevan Prakash

Abstract Adult immunization is less talked about area of health-care practice needing regular updation and implementation. It is an easy means of disease prevention which should find place as a separate topic in the medical curriculum. While the Guidelines for Immunization of Children are routinely updated and practiced clinically, the same is not true for adult immunization. The slowly waning immunity gained from vaccination in childhood, risk of exposure from frequent travels, changing lifestyles, age related immunosenescence, increasing comorbidities like diabetes and chronic kidney disease, organ transplantation and increasing use of immunosuppressive further necessitate implementation of adult vaccination measures. API guidelines recommend routine vaccination for Pneumococcal infection, Influenza, Human papilloma virus, Measles, Mumps Rubella, Diphtheria, Pertussis, and Tetanus in Adult Indian subjects. It is imperative for the related health-care associations to work together and devise a common adult which can be followed by clinicians all over the country. Physician realization, public health education about its need and government initiatives in implementation would go a long way in strengthening the infection control measures and improve the communicable disease health-related indices.

Introduction of subjects on chemotherapeutic agents or radiation therapy, further adds to these concerns. As on date the The recent pandemic of COVID-19 has exposed the status of adult vaccination in India is mostly inadequate or vulnerability of human race to infectious diseases and incomplete. In contrast to pediatric vaccination guidelines, re-emphasized that prevention is an essential part of little importance is laid on Adult Vaccination in India, even management of communicable diseases worldwide. when the mortality from vaccine preventable diseases Vaccination forms an important part of primary prevention is 350 folds higher in adults in comparison to children.2 for control of morbidity and mortality related to infectious Lack of awareness amongst general public, physician’s diseases. With increasing age, adult immunity declines apathy, meager resources, and lack of political will are (immunosenescence) and therefore there is need to impediments to implementation of adult immunization 1 address it through adult immunization. The susceptibility in routine clinical practice. Organizations like API have of populations has increased due to changing work stressed the urgent need to develop adult vaccination environment and culture involving international travels guidelines in India and its revision periodically. and explorations. The increasing numbers of organ Determinants of the vaccination needs of an individual transplant recipients, diabetics, chronic kidney disease are age, prior vaccination status, mutations in infectious (CKD) subjects, indiscriminate antimicrobial use, agents, health or comorbid illness, lifestyle, travel, emerging resistance, and growing susceptible population occupation, infection trends, disease burden in the

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population and related health-care/immunization costs. However, age wise epidemiological data relating to burden Vaccine induced immunity is neither long lasting nor broad of vaccine preventable diseases and efficacy of adult spectrum and declines with time, implying that childhood vaccination strategies in India is scant. Recent outbreaks vaccination may need to be bolstered in adulthood to of Measles (University in Karnataka, 2013-2014), Japanese provide lasting protection. In countries where last dose Encephalitis (West Bengal 2014), Influenza A (Rajasthan of had been administered at less than 2015), Varicella (Tamil Nadu 2016-2017), Diphtheria 6 years of age, a resurgence of Diphtheria in adults more (Assam 2015-2016), Hepatitis A (2015-2016) have alerted than 15 years age has been noted. Similar, increase in us to the relevance of adult immunization in India. In early average age of many vaccine preventable diseases in to 2018, around 133 outbreaks of measles, varicella, food adult life has been observed. Further, adult individuals act poisoning, and diarrhea were reported. To aggravate the as reservoirs of disease and pose a risk to the unvaccinated issue further, there is a lack of proper disease surveillance children and other family contacts in the household. and under reporting of outbreaks of vaccine preventable Likewise, the role of adult vaccination gains importance disease in India. Herein we discuss the adult vaccination in hostel facilities, residential institutions, factories, and guidelines as recommended by various organizations organizations with residential campuses. for Indian population. The recommended vaccination India contributes to 60% of Diphtheria, 40% of tetanus, schedules for clinical practice are mentioned in Tables 1 and 44% of Japanese encephalitis cases of the world.3 and 2.

TABLE 1 Summary of adult immunization guidelines7-10

Organism/Disease Vaccine Age of administration Dosage recommendations Influenza Trivalent/Quadrivalent >19 years onward; 0.5 mL IM 1 dose annually; can be given during pregnancy (FOGSI) Streptococcus PCV 13 PPSV 23 >50 years or <50 years in high risk; PCV followed by PPSV 23 at 1 years, repeat every pneumoniae 5 years Human papillomavirus 0.5 mL IM 9–14 years 2 doses 0 day and 6 months (IMA) Merck4strain/2strain GSK 15–45 years at 3 doses 0 day, 1 and 6 months, defer if pregnancy Herpes zoster 0.5 mL SC Individuals >60 years (ISN); 2 doses 2–6 months apart Diphtheria, pertussis, (Tdap/Td) 0.5 mL IM Age group >19 years; immunized Tdap once at 10–18 years; then Td 10-yearly (IMA, tetanus API, CDC), Non-immune 3 doses, 2 does 4 weeks apart followed by third at 6–12 months Tdap during each pregnancy (API & CDC) IMA adds TT/Td early during pregnancy (2 doses); Tdap during 3rd trimester of pregnancy (1 dose) Measles, mumps, and MMR 0.5 mL SC 19–60 years; 2 doses 1 month apart (ACIP); 1 dose if previously immunized rubella Pregnancy should be deferred for 3 months after immunization

TABLE 2 Immunization schedule in special situations (routinely not used)7-10

Organism/Disease Vaccine dosage recommendations Hepatitis A 1.0 mL IM; 2 doses in Adults (0 & 6 months) Hepatitis B 1.0 mL IM; 3 doses (0, 1–2, & 4–6 months) FOGSI recommends in preconception or at high risk during pregnancy Hepatitis A+B 1.0 mL IM; 3 doses (0, 1–2, & 4–6 months) Typhoid 0.5 mL IM; 1 dose every 3 years Cholera 2 separate doses of oral vaccine 1–6 weeks apart for those aged over 6 years Meningococcal 0.5 mL SC Bivalent/Quadrivalent; Adults (1 dose); At risk/asplenia 2 doses (ACIP and IMA) Varicella 0.5 mL SC; >13 years of age; 2 doses 4–8 weeks apart

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Pneumococcal Vaccination therapy. Influenza vaccines are available as trivalent (two strains of Influenza A and one strain of influenza B), Pneumonia and invasive pneumococcal disease are two quadrivalent (two strains of influenza A and two strain of dreaded complications of pneumococcal infection, which influenza B) or live attenuated (lyophilized) nasal spray account for significant morbidity and mortality, especially vaccines. Influenza vaccination is recommended in high in the immunocompromised and the elderly (subjects risk subjects, viz. CKD, chronic obstructive pulmonary >50 years of age) with a case fatality of 28%. The common disease, heart disease, immunosuppressed subjects, serotypes accounting for 55% of inpatient admissions are diabetics, and hematological disorders. Single dose needs 1, 3, 5, 19F, 8, 14, 23F, 4, 19A, and 6B. Further emerging to be administered annually to gain protection. The timing resistance to penicillin and macrolides has underlined has to be 2 weeks before the peak season for influenza the importance of adult pneumococcal vaccination. The from October to May. incidence of pneumococcal disease per lakh population is 8.8 in healthy adults, 51.4 in adult diabetics, 62.9 in subjects with chronic lung disease, and 93.7 in subjects Measles, Mumps, and Rubella with chronic heart disease.4 To reduce morbidity in high In 2018, around 55,000 cases of Measles and 1000 risk groups pneumococcal vaccination is recommend cases of Rubella were reported in India.5,6 Around 16% in subjects less than 50 years of age with chronic heart of Indian population was found to be susceptible to disease, lung disease, chronic liver disease (CLD), diabetes Rubella infection. Incidence of Mumps outbreaks has mellitus, chronic smokers, and alcoholics. been reported mainly from hostel facilities, colleges, and There are two vaccines available, viz. a PCV13 and schools in poor socioeconomic settings. A single dose of PPSV23 name denoting the number of serotype antigens triple vaccine MMR in already immunized individuals contained. The PCV13 carries a greater response, and two doses separated at interval of 1–2 month in longer immuological memory, protection against unimmunized subjects is noted to provide adequate nasopharyngeal carriage, but a lower protection against protection. invasive pneumococcal disease in elderly. A single dose of PPSV23 is recommended in Diphtheria, Pertussis, and Tetanus immunocompetent adults over 65 years of age, to be repeated at every 5 years interval. An early institution of Childhood protection through vaccination is not lifelong second dose is noted to produce hyporesponsiveness. and has been found to increase the proneness of adults Initial administration of PCV13 vaccine has been shown to Diphtheria Pertussis and Tetanus. India accounts for to amplify the response to subsequent administration of the majority of these cases in the world. A single dose PPSV23. ACIP 2015 recommends a space of 1 year between of triple antigen vaccine followed by booster every 10 the two vaccines irrespective of their order. In individuals years is noted to provide adequate protection in already who have already received PPSV23, vaccination with vaccinated individuals. PCV13 can be undertaken after 1 year interval. A prior pneumococcal conjugate vaccine (PCV13) vaccination Human Papillomavirus Vaccination followed by unconjugated capsular polysaccharide Cervical cancer is the second most common cause of vaccine (PPSV23) vaccination is recommended for high cancer and second leading cause of mortality in India. risk group with cochlear implant, CSF leaks, sickle cell Human papillomavirus (HPV) virus accounts for 90% hemoglobinopathy, asplenia, congenital, or acquired of cervical and anal cancers, 70% of vulval and vaginal immunodeficiency syndromes. cancers, and 60% of penile cancers. HPV serotypes 16 & 18 are noted to account for 77% of cervical cancers in Influenza Vaccination India.4 HPV vaccine is recommended before the onset of Annual influenza vaccination by itself has been shown sexual activity in the age between 9 and 24 years. In the to reduce cardiac mortality by 19–45% and hospital age group of 9–14 years two doses of HPV vaccine are to be admissions by 54%, which is comparable to benefit gained administered at 6 months interval. In those over 15 years from CV risk reduction by smoking cessation or statin of age three doses at 0, 1, and 6 months are advocated.

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Hepatitis A and B Vaccination need of vaccination in adulthood.1 Further the introduction While Hepatitis A virus (HAV) accounts for 10–30% of of adult vaccination is cost effective as demonstrated in 11 acute hepatitis and 5–15% of acute liver failure cases, cost benefit analysis of HPV vaccine in India. The cost hepatitis B virus (HBV) accounts for 20–30% cases of of adult vaccination is lower than the cost for childhood Cirrhosis and 40–50% cases of hepatocellular carcinoma.4 vaccination and implementation of many other secondary preventive measures (lipid lowering therapy, antihypertensives, The high prevalence of chronic Hepatitis B carrier state antidiabetics, and bisphosphonate treatment). For the adult in the population also increases the risk of transmission. vaccination to be successful it needs to overcome the barriers Hepatitis A vaccination is indicated for candidates for of (4Cs of complacency, convenience, kidney or liver transplant with chronic hepatitis B/C confidence, and cultural acceptance) which can be achieved to decrease the risk of fulminant liver failure. Also by widespread health education, evolving consensus on vaccination for Hepatitis A is indicated in illicit drug national guidelines and incorporating them in routine clinical users, homosexuals, animal handlers, persons with CLD practice. Although, as on date adult immunization is not being or other hepatitis virus infections, recipients of clotting routinely observed in clinical practice, achieving complete factor concentrates. Two doses of adult vaccination to vaccine preventable diseases through administered at 6–12 months interval gives adequate widespread implementation by medical professionals, society’s protection. schedule is 20 µg at 0, acceptance, government realization, and making vaccines affordable would make this dream come true. 1, and 6 months. Booster dose is not recommended in immunocompetent adults. Combination vaccines for HAV and HBV can also be administered in a three dose (0, 1, References and 6 months) or four dose (0 day, 7 days, 21–30 days, and 1. Boraschi D, Italiani P. Immunosenescence and vaccine failure in the booster at 12 month) schedule. elderly: strategies for improving response. Immunology Letters. 2014;162(1):346-53. Meningococcal Vaccination . 2 Bonanni P, Sacco C, Donato R, et al. Lifelong vaccination as a key disease-prevention strategy. Clin Microbiol Infect. 2014;20(Suppl. Three are available, viz. two 5):32-6. quadrivalent vaccine (against four antigens A, C, Y, and . 3 World Health Organization (WHO). Data, statistics and graphics. W135) for polysaccharide (MPSV4) and conjugate (MCV4) Available from https://www.who.int/immunization/monitoring_ or a bivalent vaccine (antigen A and C). While MCV4 surveillance/data/en/ produces lasting immunity, and reduces nasopharyngeal . 4 Koul PA, Swaminathan S, Rajgopal T, et al. Adult immunization in occupational settings: a consensus of Indian experts. Indian J carriage it cannot be used in adults more than 55 Occup Environ Med. 2020;24(1):3-15. years of age and does not provide protection against 5. Chauhan P, Gupta A, Mohan A, et al. Clinico-epidemiological study Meningococcus B strain. Therefore, MPSV4 may be of an adult mumps outbreak in a naval training establishment. J preferred in subjects more than 55 years of age or those Mar Med Soc. 2018;20(2):138-40. requiring single dose, viz. travelers. 6. Bajaj S, Bobdey P, Singh N. Measles outbreak in adults: a changing epidemiological pattern. Med J DY Patil Univ. 2017;10(5):447-52. . 7 Dash R, Agrawal A, Nagvekar V, et al. Towards adult vaccination Conclusion in India: a narrative literature review. Hum Vaccin Immunother. 2020;16(4):991-1001. The common perception that vaccination is meant only . 8 Verma R, Khanna P, Chawla S. Adult immunization in India: for children has to give way to the understanding that importance and recommendations. Hum Vaccin Immunother. vaccination has to be continued well in to adulthood. Most 2015;11(9):2180-2. of adults above 40 years of age have not received universal 9. S Arulrhaj S, Joshi SR, Shah SN, et al. API Guidelines on childhood vaccination, which was started in 1978 and could during COVID-19 Pandemic. 2020;68. attain 65% coverage only in 2014.7 Hence, the realization 10. Guidelines for vaccination in normal adults in India. Indian J that adult vaccination is urgently required needs to creep in Nephrol. 2016;26(Suppl. 1):7-14. to the community and a national program has to be carved 11. Campos NG, Sharma M, Clark A, et al. The health and economic to reduce the menace of vaccine preventable diseases. As impact of scaling cervical cancer prevention in 50 low- and much as two-thirds of Indian population is still unaware of lower-middle-income countries. Int J Gynaecol Obstet. 2017;138 (Suppl 1):47-56.

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Neurocysticercosis— 176 Clinician Recap

Alok Gupta, Deepak Kumar

Abstract Neurocysticercosis (NCC) is most common central nervous system parasitic infection caused by Taenia solium. NCC is a common cause of adulthood epilepsy with signification disease burden in developing country like India. The precise knowledge of epidemiology, clinical features, radiological correlation with stage of parasite is very helpful in effective management and reducing the burden of disease. Relational use of anti-parasitic drugs and steroids are effective in cure of NCC. This chapter is focused on clinical and radiological finding and guideline on management of NCC.

Introduction on economy and human health in India. Worldwide estimation of NCC prevalence has relatively less studied Neurocysticercosis (NCC) is caused by Taenia solium and the disease is common in India, Indonesia, most of and this is the most common helminthic infection of the Southeast Asia, part of China, many sub-Saharan Africa, central nervous system (CNS). Taenia solium is a parasite and regions of Eastern Europe.7,8 and transmission of larva stage from pig is responsible Even with advancement still there is gap between for infection in human.1 NCC is most severe form of basic and practical aspects of disease focusing, especially cysticercosis and this is a most common cause of acquired diagnosis of active lesion and appropriate timing of epilepsy in adult.2 NCC is associated with substantial antiparasitic treatment in NCC. This chapter is especially morbidity due to epilepsy, strokes, and associated focused on better understanding of disease, diagnosis, and side effects of long-term drugs therapy for seizures. treatment in clinical scenario. This disease is a major health problem in India and its prevalence in epilepsy with NCC is around 3.48/1,000 persons.3 Prevalence of NCC is higher in northern part of Etiopathogenesis India as compare to southern part of India, particularly Taenia solium, also called tapeworm, is the causative in urban population.4 The health and economic impact parasite of NCC. Both human as well as pig both act as of disease have not been assessed in depth. Past study intermediate host for Taenia solium. Adult tape worm has shown that Rs. 5,916 is the direct cost of treatment of releases the thousand of eggs in human feces. The solitary cysticercus granuloma per patient.5 pig fed the eggs contenting feces due to poor hygienic The important factors responsible for occurrence of condition. The eggs lose their covering in pig’s intestine disease in India are poor personal and social hygienic and converted into oncospheres. These oncospheres conditions. This increases scavenging pigs with use distributed in muscles of pig via blood after penetrating of partially cooked unhygienic pork.6 Further studies intestine and form cysticercus. Consumption of uncooked will require for measuring the impact of this disease pork that contained cysticercus in muscle of pig leads to

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Flowchart 1: Life cycle of Taenia solium and etiology of NCC

infection in human. In human stomach digestive enzyme encephalitis-like stage due to cerebral edema.2,12 leads evagination of their scolices. These scolices penetrate Symptomology is primarily depended up on location the gut and reach in brain and produce parenchymal and number of lesion as well as parasite load. Higher the cystic lesion (Flowchart 1). Recent studies also showed parasite load associated with strong immune response that there are person-to-person transmission of human and more severe symptoms.12 Population-based studies cysticercosis is also equally important as environmental have been shown that a substantial number of patients in source.9 Distribution of cysts in brain parenchyma occurs endemic area were asymptomatic with lesion on imaging mainly at watershed areas between gray and white matter. of brain.13 Other common sites of cyst lodgment in brain are choroid Most common clinical presentation of NCC is seizures plexus and 4th ventricle, that give rise ventricular cyst.10 and detected in up to 80% of symptomatic individual.14 In brain parenchyma, cyst has two components, first NCC is the leading cause of epilepsy in adult age 25 years is vesicular and second is scolex. The first vesicular part and more. Initially it was postulated that only viable cystic is a viable phase consists of a transparent membrane stage is responsible for symptoms and not due calcified and clear vesicular fluid and with transposed scolex. The nodules. The recent studies have been suggested that initial phase of cysticerci in brain is a colloidal stage, seizures could occur in any stage of cysticerci. Headache which may survive for many years and finally due to may be associated with or without seizure and may mimic immune response scolex get mineralized and converted the migraine. Table 1 is depicted the stage of parasite and into calcification nodule. Inflammatory response of possible mechanism of clinical manifestations. parenchymal cyst is very less and generally limited to only Focal neurological signs may be a presenting feature surrounding tissue. But meningeal cyst mostly provokes a of NCC. This has been seen up to 20% cases of NCC. severe inflammatory response in subarachnoid space and The disease course in focal neurological deficits is land up with thickened leptomeninges.11 commonly subacute or chronic and may resemble brain tumor. Pyramidal tract signs are the commonest, Clinical Manifestation of but other signs like sensory disturbances, involuntary movements, abnormal muscle tone, signs of brainstem Neurocysticercosis dysfunction, and aphasias may occur in few patients.17 Clinical manifestations of NCC are varied from Acute stroke is uncommon manifestation and occurs asymptomatic state to life threatening seizure and due to infraction in internal capsule, corona radiata,

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TABLE 1 Mechanism of clinical manifestations in NCC15,16

Stage of parasite Clinical manifestations Pathogenesis Viable cysts Seizures, hydrocephalus, focal neurological defect Mass effects cyst on the brain parenchyma Colloidal and granular Seizures, encephalitis like stage due to cerebral edema Degeneration of parasite and host inflammatory response cysts Calcified nodule Epileptogenic focus Gliosis formation around dead parasites

TABLE 2 Pathognomonic finding according to stage to parasite in neuroimaging

Stage of parasite Neuroimaging finding of brain parenchymal lesion Viable cysts A well outlined small and rounded cyst with no abnormal enchantment on contrast imaging. Invaginated scolex has seen as eccentric hyperdense nodule and called “hole-with-dot” appearance Colloidal and granular cysts The lesions are ill-defined and may be single or multiple with surrounding edema. Contrast imaging showed (degenerating) a ring enhancing or a nodular pattern of enhancing Calcified nodule Non-enhancing hyperdense nodule (better detected in CT)

and/or brainstem.18 Intracranial hypertension is a rare assay is high false negative results. Due to poor sensitivity but dreaded manifestations; either due to mass effect this cannot be used as diagnostic test but this is a very or host immune response leading to arachnoiditis or useful for monitoring of therapy, if positive in NCC.22 encephalitis.19 Neurocognitive manifestations are though Even with the advances in neuroimaging and rare and ranging from psychiatrics symptoms to severe laboratory immunological test, the diagnosis of NCC is still dementia.20 a challenging task for clinician. To improve the diagnosis accuracy of NCC, Del Brutto et al. developed a criteria Diagnosis based on clinical, radiological, immunological, and epidemiological data (Table 3). The diagnostic accuracies Diagnosis of NCC is improved significantly with increased of NCC are classified on the basis of these criteria into availability of computed tomography (CT) and magnetic definitive diagnosis and probable diagnosis. Presence resonance imaging (MRI). These investigations can of major criteria is highly suggestive of the diagnosis but be able to differentiate the stage of parasite in brain minor criteria though non-specific but required. parenchyma and this may be helpful for selection of antiparasitic therapy. Table 2 shows the pathognomonic finding according to stage to parasite in neuroimaging.21 Treatment The MRI imaging delineates better subarachnoid NCC, Because of variable presentation of the disease, a single and hydrocephalus is the most common finding. The approach is not possible for treatment. The factors affected cause of hydrocephalus is due to diffuse leptomeningeal the tailoring of treatment in NCC are location, numbers, inflammation and thickening and occlusion of the and stage of cysticerci in nervous system.23 The basis of foramina of Luschka and Magendie.17 Diagnosis of NCC treatment consist both antiparasitic treatment and ventricular cyst is also better MRI imaging and this easily symptomatic treatment. The preferred antiparasitic drugs missed in CT scan. Contrast in MRI imaging shows the are albendazole (15 mg/kg/day) or praziquantel (50 mg/ mobility of cyst within the cavities and this is called kg/day) with standard duration of treatment is 10–14 days. “ventricular migration sign.”17 In Table 4 there are some peculiar point in treatment Serological method of detection of Taenia solium guideline given by Infectious Diseases Society of America specific antibody by enzyme linked assay may be helpful (IDSA) and the American Society of Tropical Medicine in diagnosis of NCC. The major disadvantage of serological and Hygiene (ASTMH).24

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TABLE 3 Diagnostic criteria for NCC Summarized treatment guideline of NCC given by TABLE 4 IDSA and ASTMH Absolute criteria: Location of NCC Treatment recommendation zz Parasite visualization either by histopathology or funds examination of retinal or neuroimaging (scolex in cystic lesions) Viable zz In patients with hydrocephalus or diffuse Intraparenchymal cerebral edema, treat raised intracranial Major criteria: NCC pressure (ICP) (Corticosteroids) and NOT zz Radiology imaging of CNS or spine strongly suggestive of use antiparasitic treatment neurocysticercosis zz If ICP not raised, use antiparasitic zz Positive immunoblot serology for parasite treatment with adjunctive corticosteroid zz Resolution of suspected cystic lesion either spontaneously or therapy after anti-parasitic therapy Solitary cysticercus zz Antiparasitic treatment with adjunctive Minor criteria: granuloma corticosteroid therapy (Albendazole preferred) zz Radiology imaging of CNS or spine strongly suggestive of neurocysticercosis Calcified zz Symptomatic therapy alone, NOT use zz Clinical features are indicative of neurocysticercosis parenchymal antiparasitic drugs and adjunctive zz Positive parasitic antibody or antigen in CSF neurocysticercosis corticosteroid zz Presence of extra-neuronal cysticercosis Intraventricular zz Surgical removal and/or shunt surgery Epidemiologic criteria: neurocysticercosis with use of corticosteroids for treatment of brain edema in the perioperative zz Patient from high prevalent area of cysticercosis period zz History of frequent travel to high prevalent area of cysticercosis zz Antiparasitic drugs only in failure cases zz History of household contact with Taenia solium infection Subarachnoid zz Strong recommendation of antiparasitic Definitive diagnosis (any one): neurocysticercosis treatment with adjunctive corticosteroid therapy till resolution of cyst zz One absolute criterion (methotrexate could be use as steroid zz Two major plus one minor or one epidemiologic criteria sparing therapy) zz Probable diagnosis (any one): —— One major plus two minor criteria Spinal NCC zz Surgery with strong recommendation of —— One major plus one minor and one epidemiologic criteria antiparasitic treatment with adjunctive —— Three minor plus one epidemiologic criteria corticosteroid therapy

Conclusion . 3 Goel D, Dhanai JS, Agarwal A, et al. Neurocysticercosis and its impact on crude prevalence rate of epilepsy in an Indian zz Neurocysticercosis is caused by helminthic infection due to community. Neurol India. 2011;59(1):37-40. Taenia solium. . 4 Rajshekhar V, Venkat Raghava M, Prabhakaran V, et al. Active epilepsy as an index of burden of neurocysticercosis in Vellore zz Most common cause of adulthood epilepsy. district. Neurol India. 206;67(12):2135-39. zz Environmental human-to-human transmission is also 5. Murthy J, Rajshekar G. Economic evaluation of seizures associated important mode of transmission. with solitary cysticercus granuloma. Neurol India. 2007;55(1):42-5. zz Diagnosis is improved with neuroimaging, but accuracy . 6 Singh BB, Ghatak S, Banga HS, et al. Veterinary urban hygiene— required diagnostic criteria. challenge for India. Rev Sci Tech Off Int Epiz. 2013;32(3):645-56. zz Effective antiparasitic treatment with adjuvant corticosteroid . 7 Schantz PM, Wilkins PP, Tsang VCW. Immigrants, imaging and therapy is most effective treatment. immunoblots: the emergence of neurocysticercosis as a significant zz Detection of stage of parasite by neuroimaging is very public health problem. Emerging Infections. 1998;2:213-41. helpful in selection of treatment. 8. Quet F, Guerchet M, Pion SD, et al. Meta-analysis of the association between cysticercosis and epilepsy in Africa. Epilepsia. 2010;51(5):830-7. References 9. Gonzalez AE, Lopez-Urbina T, Tsang B, et al. Transmission dynamics of Taenia solium and potential for pig-to-pig transmission. Parasitol 1. Prasad KN, Verma A, Srivastava S, et al. An epidemiological study of Int. 2006;55(Suppl):S131-5. asymptomatic neurocysticercosis in a pig farming community in 10. Nash TE, Garcia HH. Diagnosis and treatment of neurocysticercosis. northern India. Trans R Soc Trop Med Hyg. 2011;105(9):531-6. Nat Rev Neurol. 2011;7(10):584-94. . 2 Del Brutto OH. Neurocysticercosis. Neurohospitalist. 2014;4(4): 11. Del Brutto OH. Neurocysticercosis: a review. ScientificWorldJournal. 205-12. 2012;2012:159821.

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12. Gripper LB, Welburn SC. Neurocysticercosis infection and 19. Garcı´a HH, Del Brutto OH. Neurocysticercosis: updated concepts disease—a review. Acta Trop. 2017;166:218-24. about an old disease. Lancet Neurol. 2005;4(10):653-61. 13. Winkler AS. Neurocysticercosis in sub-Saharan Africa: a review of 20. Forlenza OV, Filho AH, Nobrega JP, et al. Psychiatric manifestations prevalence, clinical characteristics, diagnosis, and management. of neurocysticercosis: a study of 38 patients from a neurology clinic Pathog Glob Health. 2012;106(5):261-74. in Brazil. J Neurol Neurosurg Psychiatry. 1997;62(6):612-6. 14. Ndimubanzi PC, Carabin H, Budke CM, et al. A systematic review 21. Singh G, Rajshekhar V, Murthy JM, et al. A diagnostic and of the frequency of neurocyticercosis with a focus on people with therapeutic scheme for a solitary cysticercus granuloma. Neurology. epilepsy. PLoS Negl Trop Dis. 2010;4(11):e870. 2010;75(24):2236-45. 15. Nash TE, Del Brutto OH, Butman JA, et al. Calcific neurocysticercosis 22. Tsang VC, Brand JA, Boyer AE. An enzyme-linked immuno­ and epileptogenesis. Neurology. 2004;62(11):1934-8. electrotransfer blot assay and glycoprotein antigens for diagnosing 16. Rathore C, Radhakrishnan K. What causes seizures in patients with human cysticercosis (Taenia solium). J Infect Dis. 1989;159(1):50-9. calcified neurocysticercal lesions. Neurology. 2012;78(9):612-3. 23. García HH, Evans CA, Nash TE, et al. Current consensus guidelines for 17. Fleury A, Carrillo-Mezo R, Flisser A, et al. Subarachnoid basal treatment of neurocysticercosis. Clin Microbiol Rev. 2002;15(4):747-56. neurocysticercosis: a focus on the most severe form of the disease. 24. White AC Jr, Coyle CM, Rajshekhar V, et al. Diagnosis and Treatment Expert Rev Anti-Infect Ther. 2011;9(1):123-33. of Neurocysticercosis: 2017 Clinical Practice Guidelines by the 18. Del Brutto OH. Stroke and vasculitis in patients with cysticercosis. Infectious Diseases Society of America (IDSA) and the American In: Caplan LR (Ed). Uncommon Causes of Stroke. New York, NY, USA: Society of Tropical Medicine and Hygiene (ASTMH). Am J Trop Med Cambridge University Press; 2008. pp. 53-8. Hyg. 2018;98(4):945-66.

MU-176.indd 1145 29-01-2021 15:05:11 CHAPTER

Rabies: A Comprehensive 177 Overview

Shashi Sinha, Naresh Kumar

Abstract Rabies is one of the most typical zoonotic, fatal, and acute progressive neurological infections that has been well known since ancient ages. It is avertable deadly viral disease of Rhabdoviridae family, Genus Lyssavirus. The virus uses nerve cells for their multiplication and produces mutation in the nervous system. There is no treatment for rabies, but we can avoid this by taking preventive measures. Vaccination for dogs is also available. The purpose of this comprehensive overview is to summarize the rabies and its medical importance.

Introduction „„ Keeping vaccine in freezer. If accidentally kept it should not be used. Rabies is a disease transmitted to humans through infected „„ Cauterization of the wound. animal bites (all mammals) mainly dogs (reservoirs of „„ Suturing and bandaging the wound because it may infection) pets (40%) and stray (60%). inoculate the virus deeply in to the wound. Myths about Rabies in India: „„ Debridement of the wound too much as this may cause „„ Some herbal extracts and concoctions will cure rabies. problem with wound closure and appearance. „„ People also resort to witch crafts and religious practices. „„ Storage of vaccine at room temperature. „„ Washing of wounds can cause hydrophobia. „„ Exposure to the Sun light, heat, or dust (vaccine should „„ Dietary changes can cure, that is, shift from be stored at +2–8°C) vegetarianism to non-vegetarianism or vice-versa; „„ Mixing of IMR and ID schedule. stopping consumption of white things, etc. „„ Using IG and in same syringe and at „„ A single dose vaccine will prevent rabies. same anatomical sites (it should never be practiced). „„ „„ Vaccines are more effective if taken in empty stomach. Vaccine should be diluted with the diluent provided. „„ One should avoid bathing or eating meat or eggs during vaccination. Clinical Features „„ Gems and stones have magical properties against See Table 1. rabies. Prophylaxis and Treatment Avoid: „„ To watch dog for 10 days (practically not feasible) is Questions to be Asked/to Start PET? risky and treatment should be initiated as early as The animal which bit you was pet (immunized or non possible. immunized) or stray.

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TABLE 1 Clinical features

Human beings Animals zz Hydrophobia is fear from water and difficulty in swallowing zz Rabid dogs are able to drink liquid, swim (no hydrophobia) liquid, typically unique to human beings. There are violent zz If a rabid dog is not able to drink water, it is because of the paralysis jerky contractions of the diaphragm and accessory muscles of of jaw muscles and not due to hydrophobia respiration start working zz Inability to drink is because of paralysis of jaw muscles zz Prodromal stage (2–10 days) zz Attacks without provocation and lacks direction, remains isolated zz Local pain, fever, with an inclination to vomit and refuses to eat/drink, with excess salivation zz Skin is sensitive to temperature, air currents zz Neuroloical stage (2–7 days): Aphasia, incoordination, paresis, paralysis, change in mental status, hyperactivity zz Late stage—Hypotension, coma, DIC, cardiac arrhythmia, cardiac arrest, fatality

Was the bite provoked or unprovoked? Detection of rabies virus RNA by RT-PCR is highly Did you clean/wash the wound gently/thoroughly? sensitive and specific. This technique can detect virus (This helps wash away the virus.) in fresh saliva samples, skin biopsy specimens, CSF, and brain tissues. Decision to Initiate PET? Direct Fluorescent Antibody Testing with rabies virus antibodies conjugated to fluorescent dyes is highly Should be taken well in time, as delay may increase the risk sensitive and specific. The test can be performed quickly for developing clinical rabies. PET is nearly 100% effective and applied to skin biopsy and brain tissue samples. In when used appropriately. Factors that should be taken skin biopsy samples, virus antigen may be detected in into consideration when deciding whether to initial PEG cutaneous nerves at the base of hair follicles include: „„ The epidemiological likelihood of the implicated Golden rule: It may be safest to assume that the animal that animal being rabid. bits you has rabies and treatment includes— „„ The category of exposure (I-III) „„ Local „„ The clinical features of animal. „„ Rabies shots Fast acting shot (Rabies immunoglobulin) Diagnosis -A series of rabies vaccines. Availability of the Animal for Observation and Local Treatment (Wound Toilet) Lab Testing Wash the saliva containing rabies virus and clean the During life, the diagnosis is usually made on clinical wound with soap/detergent (soaps are viricidal) and flush grounds but rapid immunofluorescent techniques can the wound under running water for at least 15 minutes. detect antigen in corneal impression smears or skin After cleaning, anti-microbial agents, disinfectant, biopsies. sanitizer can be applied. But for most cases in developing countries, the vaccination status of the implicated animal alone should Rabies Immunoglobins not be considered when deciding whether to give or The protective antibody takes 7–14 days to develop after withhold prophylaxis. initial dose of vaccine; hence, RIG should be started Examination of CSF often reveals mild mononuclear- as soon as possible because it provides activity against cell pleocytosis with a mildly elevated protein level. The rabies virus by providing passive immunity, beginning presence of rabies virus-specific neutralizing antibodies immediately after administration and lasts for about in CSF suggests rabies encephalitis, regardless of 7–10 days during which period active immunity to rabies immunization status. develops and protects the individual.

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Severe multiple bites on head, neck, face hands, and prepared from neonatal mouse brains were introduced by genitalia in particular have a short incubation period Fuenzalide et al. of only 4 days. Thus, these individuals are vulnerable to Subsequently purified (PDEC) rabies despite the timely and full course of any modern was developed, which was highly immunogenic rabies rabies vaccine and proper wound care. In these individuals vaccine that can be used safely and effectively at low doses, only RIGs are lifesaving, as their timely and proper both for primary immunization and for treatment after administration neutralizes the virus in the wounds and exposure. Subsequently, more second generation rabies prevents its progression into CNS. RIG provides protection, vaccine were developed like human diploid cell vaccine which begins immediately after administration and lasts (HDCV), vero cell, purified chick embryo cell (PCEC). for about 7–10 days, during which period active immunity PCEC vaccine with PM (Pit men-moore) strain. to rabies develops and protects the individual. Advantages: Often, this failure of modern cellular vaccines in most „„ It is more advantageous than many other cell line cases has been because RIG was not use in high risk based rabies vaccines. category III cases „„ It is more readily scalable to large scale commercial There are two types of RIGs: vaccine production. „„ The vaccine produced by the present process has a „„ ERIG (Equine Rabies Immunoglobulion): very large yield, efficacy safety as well as the process is —— It is heterologous in origin much cost-effective than many of the other processes —— Produced from hyper immunized horses known for the preparation of rabies vaccine. —— Economical as compared to HRIG; hence, more „„ It has unique stabilizing agents, which make the affordable vaccine more stable even at accelerated temperature. —— The currently manufactured ERIG are highly „„ This method provides vaccine with high yield, greater purified with least adverse effects. Most of the potency, and immunogenicity, which make the ERIG available are F(ab’)2 fragment free from vaccine cost-effective and unique. reactogenic Fc fragment All modern anti-rabies vaccines are freely inter­ —— Dose is 40 iu/kg body weight up to a maximum of changeable. The safest vaccine, free of complications, is 3,000 iu (given after sensitivity test) human diploid cell stream vaccine. „„ HRIG (Human Rabies Immunoglobulin): —— Homologus in origin Vaccines can be given: —— Longer half-life when compared to ERIG; hence, „„ In pregnant woman given in half the dose of ERIG „„ In lactating woman —— Does not require prior skin testing „„ Along with other vaccine (EPI, i.e., expanded program HRIG are imported, expensive, and scarce. on immunization) vaccines „„ Dose is 20 iu/kg body weight up to a maximum of 1,500 „„ To a child with chicken pox or measles iu. „„ To HIV +ve or AIDS patients RIGs should be given as a single dose and should not „„ To patient with jaundice be repeated. „„ To patients who are on antimalarials or steroids or taking immunosuppressive drugs. Generally, vaccine should be avoided with these drugs but if cannot be Vaccines avoided then vaccine on day 0 may be doubled and Human rabies vaccines are made from inactivated or given at two sites attenuated rabies virus and have gone through successive „„ With a higher potency improvements since the time of Pasteur. The first rabies Indications for doubling the first dose (0 dose) of rabies vaccine was developed by Pasteur, which was nerve tissue vaccines: based and virus was inactivated by drying, but this vaccine „„ Patients who seek treatment after a delay of 48 hours or had a risk of activation of the virus and allergic reaction to even months after having been bitten should be dealt the presence of nerve tissue or myelin. Myelin-free vaccine in the same manner as it expose occurred recently.

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„„ Patients with very high risks exposures on extensive being very hazardous and in humane. Saturated solution bites. of magnesium sulfate administered IV is the ideal and „„ Immunodeficient patients, or those on immuno­ recommended method for killing dogs. After destroying suppression drugs, e.g., antimalarials, anticancer the dogs, the concass should be hygienically disposed off. drugs, etc. But this is not allowed. „„ Severely malnourished patients. The dog destruction used to be one of the pivotal „„ Patients with underlying chronic disease like cirrhosis activities at the primary health center in India. Sanitary of liver. inspectors used to destroy dogs in rural areas after „„ Patients where RIG is indicated but unavailable. obtaining the requisition from village panchayats. Now this has been stopped. Human way of dog destruction is Discussion: Rabies is one of the oldest diseases known in in practice in municipal areas. No solution seems to be recorded medical history. It is caused by a bullet shaped in hand to destroy stray dogs in rural areas, the menace RNA rhabdovirus that is a member of the rhabdoviridae continues to grow. Similarly, monkey menace has been family, genus lyssavirus. Generally, rabies is transmitted additional burden in urban areas, besides dogs. by saliva from infected animal bites but may also be Municipal authorities hold the responsibility of dog transmitted by scratches, secretions that contaminate catching licensing and dog destruction by humane way to mucous membranes, aerosolized virus that enters the prevent cruelty against animals. respiratory tract and corneal transplants. Sterilization of dogs and monkeys has been attempt to Rabies is a neglected disease of poor and vulnerable reduce their population. population whose deaths are rarely reported. It occurs mainly remote rural communities where measures to prevent dog to human transmission have not been implemented. Under Pre-exposure Immunization in Animals reporting of rabies also prevents mobilizations of resources Pre-exposure immunization of pet animals against rabies from the international community for the elimination of is recommended. human dog mediated rabies. Single dose: The vaccine is prepared as 20% suspension of brain from sheep infected with modified rabies virus. Prevention of Rabies The virus in the brain suspension is inactivated phenol This consists of: or B-propiolactone (BPL). It’s only used for pre-exposure „„ Elimination of stray dogs immunization. „„ Registration and licensing of dogs „„ Immunization of dogs and pets Veterinary Antirabies Vaccine Multiple Dose Since dogs are the major reservoir of rabies trans­ This vaccine is also prepared from sheep brain infected mission in India (Table 2), there population must be with modified rabies virus. The virus in the vaccine is controlled. Way back in 1985, the dog population was killed with phenol or BPL. The vaccine is given in multiple estimated to be 80 million as per census by agriculture doses and can be used for both pre- and post-exposure ministry. It appears this population might have grown immunization of dogs, cats, and other domestic animals. substantially. This vaccine confers higher degree of protection than For killing of dogs strychnine had been in use for long conferred with single dose vaccine. time, its use is not advocated these days because drugs Epidemiological cycles: „„ Urban: As many as 99% of human cases in India are TABLE 2 Reservoir animals due to bites by urban rabid animals, which maintain

Frequently Sometimes Occasionally Not reported a cycle amongst themselves. DOG→DOG→Other animals, and man being an accidental victim and dead Dogs Monkeys, Camels, Bats, Rodents, Cats Horses, Sheep, Elephants, Foxes, Birds end of infection. Cow, Buffaloes, Mangoose, „„ Sylvatic: Cycle propagates itself within wild animals Donkeys, Pigs Jackals, Bears who sometimes transmit the infection to urban

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animals as well as man. Bat rabies has not been zz Taking right steps at right time can reduce exposure to conclusively reported from this country. No courier infection and prevent rabies. state has been convincingly demonstrated in dogs and zz When in doubt about the degree of exposure to rabies risk, in all practical purposes it is taken as non-existent. it is safer to over treat that to under treat. Mode of transmission: zz Criterion for “protection” after immunization—is that the rabies virus neutralizing antibody (RVNA) titer of „„ Licks on damaged skin and mucous membrane or ≥0.5 iu/mL of serum in the vaccinated person which is scratch considered protective. „„ Directly from the bite by Rabid animals zz Person receiving/completed anti-rabies immunization „„ Handling saliva of rapid animals or patient either pre-exposure or post-exposure can donate blood, „„ Organ transplantation particularly by corneal graft etc. but the recipient does not benefit from the transfer of rabies „„ Unboiled milk of Rabid infected cow neutralizing antibodies due to hemodilution. zz Health education of public on prevention and control of „„ Urine, tears, nasal secretions, and sweat rabies and management of bites and their response to bite „„ Aerosol contamination at local level is crucial to save lives. This should be through „„ Mechanical transmission primary health-care infrastructure besides mass media as After local multiplication at the wound site, the virus also formal and non-formal education channels. enters the nerves and travels at the rate of 3 mm/hours zz In developing countries, where human rabies globulin to the dorsal root of ganglion, then reaches the anterior may not be obtainable, 0.1 mL of vaccine may be given horn cells of the spinal cord and brain, developing rabies intradermally into eight sites on day 1, with single boosters on days 7 and 28. encephalitis, and inevitable deaths. Incubation period: On an average 20–90 days, but 4 days to 8 years have been reported. Suggested Readings . 1 Alagappan R. Manual of Practical Medicine. Jaypee Brothers Pathology Medical Publishers Pvt Ltd: Delhi; 2018. 2. Jameson JL. Harrison’s Principles of Internal Medicine, 20th edition. „„ Minimal pathologic changes 2018. „„ The brain is edematous and congested on gross . 3 Park K. Park’s Textbook of Preventive and Social Medicine. Bhanot appearance Publishers: India; 2015. „„ Histopathologically: 4. Prabhakara GN. Short Textbook of Preventive and Social Medicine. 2010. p. 444. —— Perivascular cuffing and gliosis 5. Rabies immunoglobulin manual, IJCP academy of CME. —— Minimal neuronal damage (necrosis) . 6 Ralston S, Penman I, Hobson R, et al. Davidson’s Principles and —— Presence of Negri bodies is pathognomonic Practice of Medicine, 23rd International edition. 2018. p. 1440. . 7 WHO guide for pre and post exposure prophylaxis in humans. WHO. 2010. Available from: https://www.who.int/rabies/PEP_ Conclusion prophylaxis_guidelines_June10.pdf zz A much feared disease known to man since ancient times 8. WHO guide for pre and post exposure treatment in humans. WHO. is rabies. 2002. . 9 WHO recommendation on post exposure treatment:WHO/ zz A deadly disease, but also a 100% preventable disease. EMC/200/96.6.

MU-177.indd 1150 29-01-2021 15:05:06 CHAPTER

Biomarkers for Diagnosis and 178 Prognosis of Severe Malaria

Manoj Kumar Mohapatra

Abstract Biomarkers are different cellular, biochemical, or molecular products, which are measured in different biological samples to assess the diagnosis and prognosis of malaria.

Introduction disease. There is no suitable classification of biomarkers. However, Frank and Hargreaves have attempted to classify Malaria is an intricate parasitic disease caused by the biomarkers into the following three types:2 intraerythrocytic parasite of the genus Plasmodia. „„ Type 0: Measures of natural history of the disease and Five species, Plasmodium falciparum, Plasmodium correlate with clinical outcome. vivax, Plasmodium malariae, Plasmodium ovale, and „„ Type 1: Determines the biological effect of therapeutic Plasmodium knowlesi, are responsible for human malaria. intervention. Almost all deaths due to malaria are caused by falciparum „„ Type 2: Characteristic or variable that reflects how a malaria, and, despite all efforts, still it persists as a disease patient feels/functions/survives, i.e., a clinical end of high mortality. Improper diagnosis and development point. of drug resistance are two factors that make the disease 1 difficult to control. Biomarkers for Malaria For a long time, detection of the parasite in peripheral blood smear has been considered as the gold standard In malaria, host and parasite interaction is of paramount of diagnosis but with a lot of limitations. Further, definite importance. Therefore, biomarkers related to the parasite indicators of bad prognosis factors are necessary for may be used for diagnosis and from the host may be utilized for prognosis. When parasite enters the human body, prognosis of patients of severe malaria. Therefore, there is parasitic proteins trigger the host immune systems, which necessity of detecting different biomarkers for diagnosis are associated with malarial pathogenesis and severity. and prognosis of malaria. The molecules released during pathogenesis can be used as diagnostic biomarkers. P. falciparum severe infection Biomarkers has diverse effect on multiple systems causing multiorgan Biomarkers may be defined as different cellular, failure. Molecules released during complications like biochemical, or molecular alterations, which can be cardiac dysfunction, circulatory dysfunction, kidney measured in different biological samples to assess the dysfunction, and alteration of cell signaling can be used as diagnosis, prognosis, or therapeutic responses of a prognostic biomarkers or biomarkers of severity.3

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Criteria for an ideal biomarker: An ideal biomarker should patients. Its release in abundance makes it an important be: parasite antigen for diagnosis of malaria. „„ Less costly „„ Easy to detect and evaluate Parasite Lactate Dehydrogenase (pLDH) „„ Can be used in low-resource settings Normally, the requirement of glucose for the metabolism „„ It can be used at the point of care of RBC is modest. But after the invasion, plasmodium „„ It should have the power to distinguish different forms consumes an excess amount of glucose for its growth of the disease like symptomatic versus asymptomatic and metabolism. The extra glucose has been taken from or uncomplicated versus severe malaria the blood by the parasite and metabolized by anaerobic „„ It should provide better prognosis glycolysis and glucose is converted to lactic acid and „„ It can guide treatment excreted to circulation. The final enzyme of this glycolytic Biomarkers used for diagnosis are HRP II (Histidine rich pathway is lactate dehydrogenase, and hence is over protein II), Parasite Lactate dehydrogenase, Hemozoin, expressed and can be used for diagnosis purpose.5 Aldolase, Haptoglobin.4 Biomarkers used for severity of disease are vascular Hemozoin dysfunction (angiopoetin-Tie-2 system), RBC membrane The parasite infects the RBCs and digests hemoglobin dysfunction (gamma GT), serum uric acid, eGFR, resulting in release of amino acids and toxic-free heme Procalcitonin, lipase, cardiac markers (PPARG coactivator (ferriprotoporphyrin IX), which is polymerized to 1 alpha, CPK-MB), Apoptosis markers (DAPK1; death hemozoin. It helps the parasite to survive from the heme associated protein kinase-1), hypoxia and cerebral toxicity. It plays a role as a visible marker in identifying malaria (HRP II, IFN-gamma, Lymphotoxin-alpha, parasites; therefore, popularly termed as malaria pigment.3 chemokine CXCL10), neurological dysfunction (ApoE, apolipoprotein). Other Biomarkers Biomarkers to assess protective immunity are antibodies Apart from these, Aldolase and Glutamate dehydrogenase to ICAM-1 binding P. falciparum erythrocyte membrane are two enzymes, which can be used for diagnosis purpose. protein-1 (PfEMP-1) and to glycosylphosphatidylinositol 5 (GPI). Haptoglobin Diagnostic Biomarkers Haptoglobin (Hp) is an α2 glycoprotein that binds rapidly to free hemoglobin (Hb). After rupture of parasitized RBC Histidine Rich Protein and hemolysis of non-parasitized RBC, free Hb binds to P. falciparum synthesizes a unique set of soluble HRPs Hp forming a complex which is rapidly cleared by the during the asexual erythrocytic development. There are mononuclear phagocytic system, resulting in a state of three types of HRP, namely HRP I, II, and III in the order hypohaptoglobinemia, which can be used as a clinical and 6 of discovery.4 epidemiological biomarker of falciparum malaria. HRP-I is also known as knob-associated protein. It produces knob like protrusions on the cell surface of Biomarkers of Severity and Prognosis parasitized RBC that helps in cytoadherence of infected In addition to the diagnostic performance, biomarkers erythrocytes to venular endothelium. HRP-II helps in have been identified for the prognosis of severe malaria. heme binding and heme detoxification by hemozoin Endothelial cell activation is crucial in pathogenesis of formation. It is exclusively found in P. falciparum. HRP- P. falciparum malaria. Activation of endothelial cells III, also known as small histidine alanine rich protein causes release of procoagulant and inflammatory proteins (SHARP) was found to have polymorphisms in gene like tissue factor, Ang-2 (angiopoetin-2), I-CAM, and repeats and shares homology with HRP-II. E-selectin. Amongst these HRPs, HRP-II was found to be Ang-1 and Ang-2 are ligands of the Tie-2 receptor which transported from parasite through the host cell cytoplasm is expressed on endothelial cells. Ang-1 is constitutively to the circulation and can be detected in urine of infected produced and excreted into blood by pericytes and

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smooth muscle cells and also stored in platelets. It binds to an extracellular signal trigger, DAPK1 is phosphorylated, Tie-2 receptor, thereby acting as agonist resulting in anti- which increases its catalytic activity and causes cellular apoptotic and anti-inflammatory status of endothelial death mediated by p53 pathway. When there is an cell. Ang-2 is produced in endothelial cell and prestored increased parasite burden, there is inhibition of DAPK1 in Weibel Palade Bodies (WPB) together with vWBF. and p53, a strategy of parasite survival during metabolic Upon endothelial activation, there is exocytosis of WPB, stress. Therefore, decrease in apoptotic markers DAPK1 Ang-2 released and replace Ang-1-Tie-2 interaction. This and p53 signify severe malaria. interaction stimulates inflammatory response. Further Apo-E is a major lipoprotein in brain and has been seen studies based on this pathogenesis showed that decreased dominant in several neurological diseases. Hence, several Ang-1 and increased Ang-2/Ang-1 ration are robust studies have been carried out to assess its correlation with biomarkers to distinguish uncomplicated malaria from cerebral malaria as a neurological biomarker.5 cerebral malaria. However, they do not correlate with parasitemia.7 PCT is a prohormone of calcitonin containing 116 Biomarkers of Protective Immunity amino acids with a molecular weight of 13 kDA. Under „„ Antibodies to ICAM-1 binding PfEMP1-DBL beta: physiological conditions, calcitonin is produced and Expression of diverse P. falciparum erythrocyte secreted from C-cells of thyroid gland after intracellular membrane protein-1 (PfEMP1) gene variants proteolysis to circulation with plasma half-life of a few allows clonal antigenic variation and cytoadhesion minutes. Therefore, under normal condition PCT level to endothelium. Adhesion occurs via specialized is low (<0.5 ng/mL). The origin of PCT in infection is PfEMP1 domains known as duffy binding like (DBL) thought to be extrathyroidal and the predominance of and cysteine rich interdomain region (CIDR) and PCT without increase in calcitonin indicates the presence antibodies against them are significantly associated of a constitutive pathway within the cell that bypasses the with protection against severe malaria. This class enzymatic conversion of PCT to calcitonin.8 of DBL beta domain could be used as diagnostic High negative predictive value of S.PCT may be helpful antigens.3 for a rapid exclusion of critical malaria on admission. „„ IgG antibodies to synthetic GPI: In malarial parasites, When S.PCT was ≤2 ng/mL the patients can be managed GPI is a glycolipid that is found both free and as an in the general ward or domiciliary treatment may be given; anchor sustaining many proteins on the parasite with 2–10 ng/mL the patients can be managed in the membrane including merozoites. In animal studies, it general ward with special attention or in high dependency has been found that antibodies against GPI were able to unit (HDU) and can be shifted to ICU when necessary; and delay mortality by P. berghei, by blocking toxic immune if more than 10 ng/mL the patients should be shifted to ICU response. Further studies showed that GPI was found 9 for management. Different biochemical investigations to be present across all stages of malarial parasite life that determine dysfunction of different organ systems can cycles suggesting that antibodies against GPI could be be used as biomarkers of severity. able to prevent both erythrocytic and hepatic infection Elevated level of gamma glutamyl transferase (GGT) and block transmission of parasite from human to was observed when there is increased RBC membrane mosquito. These observations highlight that IgG to GPI damage contributed by oxidative stress. Markers of can be potential biomarkers of immune status.3 liver dysfunction like serum LDH and total bilirubin is significantly elevated in severe malaria. Serum lipase, a Conclusion pancreatic enzyme which has been associated with acute pancreatitis, a rare complication of P. falciparum can be Unlike other diseases biomarker research in malaria is used as a biomarker.10 Cardiac biomarkers like PPARG slow. However, recently biomarker research on malarial coactivator 1 alpha and CPK-MB are significant cardiac pathogenicity has taken a leap as evidenced by discovery of biomarkers indicating of severe malaria and can be used HRP-II, pLDH, aldolase, hemozoin, angiopoietin, procalcitonin, etc. Further, it is now important to distinguish complicated and as biomarkers.11 cerebral malaria as early as possible so that treatment can be DAPK1 (death associated protein kinase 1) is known implicated to reduce the mortality. as a mediator of apoptosis and autophagy. When there is

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References 6. Mohapatra MK, Mohanty S, Mohanty BK, et al. Hypohaptoglobinemia as a biochemical and epidemiological marker of falciparum malaria. . 1 Severe falciparum malaria. World Health Organization, J Assoc Physicians India. 1999;47(9):874-7. Communicable Diseases Cluster. Trans R Soc Trop Med Hyg. 7. Mohapatra MK, Gnanasekaran GS, Mohanty PK, et al. Angiopoietin-1 2000;94 (1):1-90. and -2 in falciparum malaria: its dysregulation and role as . 2 Frank R, Hargreaves R. Clinical biomarkers in drug discovery and biomarkers for prediction of outcome. SF J Med Res. 2020;1:1014. development. Nat Rev Drug Dis. 2003;2(7):556-80. . 8 Muller B, White JC, Nylen ES, et al. Ubiquitous expression of the . 3 Jain P, Chakma B, Patra S, et al. Potential biomarkers and their calcitonoin-1 gene in multiple tissues in response to sepsis. J Clin application for rapid and reliable detection of malaria. Biomed Res Endocrinol Metab. 2001;86(1):396-404. 9. Mohapatra MK, Thomas AG, Bariha PK, et al. Serum procalcitonin: as Int. 2014;2014:852645. a triage tool for severe Plasmodium falciparum malaria. J Tropical 4. Howard RJ, Uni S, Aikawa M, et al. Secretion of malarial histidine rich Dis. 2013;1(4):1-4. protein from plasmodium falciparum infected erythrocytes. J Cell 10. Mohapatra MK, Gupta MP. Falciparum malaria complicated with Bio. 1986;103(4):1269-77. acute pancreatitis. J Vector Borne Dis. 2011;48:177-9. 5. Bharadwaj N, Zohaib MD, Sharma S, et al. Clinicopathological study 11. Mohapatra MK, Mohanty NK, Das SP, et al. Myocardial injury: of potential biomarkers of plasmodium falciparum severity and an unrecognized complication of cerebral malaria. Trop Doct. complications. Inf Genet Evol. 2019;77:104046. 2000;30(3):188-9.

MU-178.indd 1154 29-01-2021 15:04:53 CHAPTER How Fatal Is Plasmodium vivax—To Be Understood and 179 Its Management

Smita Gupta, Neeraj Kapoor, Ankit Grover

Abstract Malaria caused by Plasmodium vivax is often a life threatening disease leading to significant mortality in our society. Though severe malaria has been attributed to Plasmodium falciparum; however, mortalities and complications associated with vivax malaria cannot be overlooked. The ability of vivax to remain dormant in the form hypnozoites causing relapse and increasing complications by cytoadherence and rosette formation further adds to the disease burden. Chloroquine resistance is an emerging challenge in the management of patients with vivax malaria. Complications like hemolysis, cerebral malaria, ATN, and acute respiratory distress syndrome are also now attributed to Plasmodium vivax malaria.

Introduction P. falciparum known to cause Severe Malaria has been contributing to maximum morbidity and mortality Malaria is a life threatening protozoal disease caused by worldwide whereas infection by P. vivax is always thought Plasmodium parasite, which is transmitted to humans to be a benign disease, classically causing mild symptoms. by bite of an infected female Anopheles mosquito. Of But recently it has been seen that the infection by P. the five parasite species that cause malaria, two of them, vivax no longer results in a non-critical illness having so Plasmodium falciparum and Plasmodium vivax, pose many case reports showing its association with severe life the greatest threat. World Malaria Report 2019 states threatening complications. There are historical evidences that nearly half the population of the world was at risk of too, showing its severity which come from reports on exposure to malaria in 2018.1 An estimated 228 million neurosyphilis therapies in early 1990s reporting 5–15% cases of malaria were there worldwide in 2018 in contrast mortality rates in America and European treatment to 231 million cases in 2017 of which around 405,000 facilities using P. vivax for treatment of syphilis indicating deaths globally due to malaria. Currently, India accounts that it always had a severe outcome.4 for 4% burden of malaria globally and 87% of the Southeast Asia.2 Most vulnerable group includes children less than 5 years of age accounting for 67% of deaths due to malaria Plasmodium vivax : Epidemiology worldwide.1 The most prevalent parasite in African region The most widespread infections of all malarial parasites is is P. falciparum (99.7%), whereas P. vivax remains as the P. Vivas which affects majority of the parts of subtropical prevalent parasite in America, accounting for 75% of all & tropical areas of the world. Nearly 2.5 billion people are malarial cases.1 In India, malaria is a major health problem affected by P. vivax infection in the world and 16 million with 0.88 million cases occurring per year. Severe Malaria clinical cases occur annually.5,6 Highest burden is borne by (as per the WHO guidelines) accounts for approximately Southeast Asian countries and South America out of which 400–1,000 deaths per year3 and most of them are due to P. 53% of cases occur in South East Asia with India alone falciparum. bearing around 47% of the total burden.5,6 it has a wider

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geographical variation and distribution due to its ability to months and years.14 The variation in time of relapse varies stay dormant in liver cells and then cause relapses and its from one region to another and it is observed that in capability to survive in cold weather. As per the studies, it tropical countries the dormant period of relapse is usually has been reported that many people in Africa are resistant 8–10 months.15,16 The exact mechanism how hypnozoites to P. vivax infection due to absence of Chemokine Duffy initiate relapses is still unknown. antigen receptor on RBCs but this theory has been put to question by many reporting cases in Duffy negative Increased Pyrogenicity 7,8 patients also. In contrast to P. falciparum, which is known to invade In 2014, there were 2.14 million cases of P. vivax all stages of erythrocytes, and as a result parasitemia can 9 worldwide, 18% of them occurred in India alone. In the exceed as high as 20–30%, P. vivax is known to invade recent past the number has been increasing accounting the reticulocytes rather than the erythrocytes, resulting for nearly half of all the malarial cases. The incidence of in lower parasite biomass and parasitemia, which rarely P. vivax varies across India with ten states accounting for exceed 2–3% in blood even in severe infection. P. vivax 10 nearly 89% of total cases. Out of these Jharkhand, MP, in spite of having lower pyrogenic threshold has been Odisha, UP, and Gujarat carry 64% of the total burden. It observed to have higher endothelial activation, increased is becoming a problem mainly in urban settings of India production of cytokines, and a proinflammatory response probably due to construction work, migration, and ever as compared to P. falciparum.14 The main reason could growing slum areas, and resulting in peaks in morbidity be presence of higher levels of genomic content (GC) in and mortality. Within the Urban Malaria Scheme, 98% of vivax genome, and thus having higher contents of CpG 10 all malaria cases were P. vivax in 2014. Its transmission motifs, which are recognized by receptor 9 leading to occurs throughout the year, but it peaks during rainy or cell activation and inflammatory responses.17-19 Toxins post-rainy seasons. contributing to increased pyrogenicity of P. vivax have been found to be cholesterol or triglyceride fraction of Risk Factors and Pathophysiological plasma at the time of paroxysm of fever.14 The imbalance Mechanisms Leading to Its Malignant between pro- and anti-inflammatory cytokines production is related to severe clinical conditions in P. vivax.20 Course P. vivax infection now poses a great threat with multiple Sequestration and Rosetting Phenomenon reports showing severe clinical presentations and deaths. The classical pathogenesis of severe P. falciparum infection 11 A meta analysis published in 2014 showed that P. vivax leading to “Severe Malaria” shows sequestration of parasite as a major cause of “Severe Malaria” and warranted a in endothelial tissue causing microvascular obstruction, prompt and early detection of its clinical manifestation inflammation ultimately resulting in hypoxemic, and resulting in early initiation of therapy so that it could be life ischemic damage in organs. Similar studies are now saving. Many risk factors have been discussed related to documenting that there is binding of vivax infected RBC to its severe course. Children below 5 years of age are at risk endothelial cells via receptors like ICAM 1 but to a much of developing critical illness and ultimately dying within lesser frequency than the P. falciparum infected RBCs.21 12 1 year of their initial presentation. Genetic polymorphism They also seem to be attached to glycosaminoglycans varies and shows alpha and beta thalassemia patients like chondroitin sulfate and hydraulic acid.22 Severity of having increased risk and Duffy negative and G6PD P. falciparum is associated with the above phenomena, deficient patients having decreased risks of P. vivax which is also seen in P. vivax but it shows a moderate 13 infection. level of cytoadherence to endothelial cells and ultimately resulting in inflammatory responses in organs like lungs. Relapse In fact this phenomenon of sequestration and adherence The ability of P. vivax to persist as dormant stage as of infected RBCs and accumulation of malarial pigment hypnozoites in liver initiates infection in the blood deposits to the intervillous spaces of placenta has been resulting in frequent relapses ranging from weeks to associated with pregnancy induced malaria leading to

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anemia and intrauterine growth retardation although it its explanation in spite of low parasitemic index. Also appears to be less severe.14 its tendency to relapse usually at 3–4 weeks interval Apart to adhesion phenomenon, it is also known that repeats the cycle before the hematological recovery vivax too has a tendency to form rosettes, which has been takes place from previous infection. Inflammatory mentioned in literature more than 20 years ago,23 although cytokines also result in dyserythropoiesis and bone seen more frequently with falciparum. Rosettes in P. vivax marrow suppression.31,32 Usually a palpable spleen is are formed by interaction of infected RBCs containing found several day after infection but many of the otherwise trophozoites, schizonts, or gametocytes. The rosettes of healthy individuals have been found to have a palpable P. vivax are stable even under high physiological shear spleen indicating repeated infections in an endemic area. stress and cause increased rigidity of infected RBCs Mild hepatomegaly may be observed in children. Mild thereby contributing to sequestration of P. vivax in the jaundice may be seen in adults and usually resolves in 1–3 24 microvasculature. weeks indicating uncomplicated infection. P. vivax also has pulmonary complications and the Chloroquine Resistance spectrum ranges from cough, acute breathlessness, The recommended drug in management of both P. pulmonary edema to ARDS, and death. A meta-analysis falciparum and P. vivax is chloroquine, but now resistance published in 2017 showed that out of 49 studies 59.1% has started developing to this drug especially in endemic case studies reported acute respiratory distress syndrome areas. This is attributed to presence of polymorphism (ARDS), 20.4% respiratory distress, 4% respiratory failure, in chloroquine resistance genes pvcrt-0 and pvmdr-1 in 2% lung injury, and 2% studies reported pulmonary 25 South India. edema.33 They concluded that respiratory complications and ARDS occur in lower frequency in vivax than in Clinical Manifestations and Complications falciparum, but mortality resembles that of falciparum. Fever is the main complaint of malaria and symptoms Female gender, presence of comorbidities, respiratory start to appear as soon as the blood stage infection starts complications at time of hospital admission, and low- with the invasion of RBCs by the merozoites. As the life hemoglobin level were associated with deaths. Another 11 cycle of P. vivax repeats every 42–56 hours, the paroxysm meta-analysis was published in 2014 in which three of febrile episodes occurs during similar intervals and studies showed higher incidence of ARDS among P. 34-36 classically the fever is termed as the tertian fever.26 Fever is vivax as compared to P. falciparum. The presence usually intermittent, may go as high as 40 degrees in non- of lymphocytes, neutrophils along with phagocytosed immune individuals and children associated with chills pigments in the pulmonary vasculature is the main and rigors followed by profuse sweating and weakness. cause of direct damage to lung parenchyma, diffuse 37 Other non-specific clinical features include abdominal inflammation, and alveolar damage. discomfort, malaise, fatigue, and muscle aches. In few Acute kidney injury (AKI) remains a major cause of patients, a prominent headache, altered sensorium, or morbidity and fatality with incidence ranging from 15% 38,39 irritability may be observed. Headache may be very severe to 40% in numerous studies. Mostly it is due to P. but usually signs of meningeal irritation like neck stiffness falciparum, but AKI has been reported in 12–20% P. vivax and photophobia are absent. infection also, whether it is due to solely vivax or mixed In areas of high-relapse rate, anemia has been observed infection is still debated. Mortality associated with P. vivax to be the most common finding in both children and AKI is 10–15%, which is comparable with P. falciparum39 adults. The most likely causes involved are cumulative and 10–20% may require renal replacement therapy. losses of infected RBCs, lysis of uninfected RBCs, and Kidney complication are mainly due to hemodynamic defect in production of red cells.27-30 It is said that for dysfunction and immune response and clinically they every one infected RBC in circulation, approximately present as oligoanuria, severe metabolic acidosis, and 34 uninfected RBCs are removed and thereby leading hypercatabolic state.40 A study conducted in 201741 to severe anemia. A higher inflammatory response, in discussing the clinic histologically profile on 30 patients the spleen leading to higher losses of RBC, seems to be showed fever in all cases, oliguria in 23%. Renal biopsy

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performed among 6 patients revealed features of ATN in 4 species and are time saving without the requirement of a patients, one had features of thrombotic microangiopathy, skilled lab personnel.26 This test has a high sensitivity at while one revealed acute cortical necrosis. Another higher parasitic load and may give false negative at lower study42 conducted showed that a high index of suspicion parasitic load. This test can be positive even 1 month after for diagnosing thrombotic microangiopathy should be successful treatment. A new recently developed real time kept if patient has persistent anemia, thrombocytopenia, micro PCR based diagnostic device has been claimed to jaundice, and non-recovering renal failure, such patients have high sensitivity and specificity.48 usually respond to plasmapheresis. The inciting event may 3 be the lesion in endothelium of renal microvasculature. Treatment of P. vivax Cerebral malaria a complication of P. falciparum, The objective of treating malaria caused by P. vivax is to characterized by diffuse meningoencephalitis, is seen to cure both blood stage and liver stage infections thereby occur with P. vivax also.43 The patient usually presents preventing recrudescence and relapse both, respectively. with signs and symptoms of acute febrile encephalopathy, The ability of P. vivax to from hypnozoites possesses a seizures, and coma. Focal neurological deficits are unlikely. great challenge in management of patients. However, a case presenting with Status Epilepticus WHO Malaria Treatment Guidelines, 3rd edition,3 has been described.43 Though the exact pathogenesis suggest treatment of all suspected and confirmed remains elusive, but similar pathogenesis of sequestration uncomplicated malaria patients with chloroquine or of infected erythrocytes have been described.44 One Artemisinin Combination Therapy (ACT). pathogenesis regarding cerebral malaria is genetic 3 variation resulting in variant interspersed repeats genes, Chloroquine Sensitive Malaria the largest subtelomeric multigene super family found in Oral chloroquine at total dose of 25 mg/kg (initial dose of P. vivax.45,46 10 mg/kg on first day followed by 10 mg/kg on second day So it is understood that features of Severe Malaria can and 5 mg/kg on third day) (Box 1). also be seen in P. vivax infection as commonly found in ACTs are highly effective in the treatment of vivax P. falciparum leading to multiorgan involvement. A study malaria, allowing simplification (unification) of malaria conducted in 2019 among 150 patients showed Severe treatment, that is, all malaria infections can be treated Malaria among 42% of cases (as per WHO criteria) with with an ACT. The exception is artesunate + sulfa­ mortality of 1.33%.47 doxine pyrimethamine, where resistance significantly compromises its efficacy. Management and Treatment Chloroquine Resistant P. vivax 3 Main pillar in elimination of malaria is early diagnosis and treatment thereby reducing disease burden and preventing ACTs containing piperaquine, mefloquine, or lumefantrine complications, and deaths. Malaria is a notifiable disease are the recommended treatment, although artesunate + in India. For diagnosis, uses of light microscopy or amodiaquine may also be effective in some areas. immunochromatography-based rapid diagnostic tests 48 (RDTs) are being used. The gold standard for diagnosis is Treatment uncomplicated P. vivax, P. ovale, P. BOX 1 direct visualization of P. vivax parasites on Giemsa stained malariae or P. knowlesi malaria blood smears by light microscopy. It is a low cost with high zz In areas with chloroquine-susceptible infections, treat adults sensitivity diagnostic test. Parasitemia is detected by thick and children with uncomplicated P. vivax, P. ovale, P. malariae, or smears and at least 200 fields should be examined well P. knowlesi malaria with either an ACT (except pregnant women before concluding negative diagnoses. Thin smears are in their first trimester) or chloroquine. used to calculate the parasite density. The parasite density Strong recommendation, high-quality evidence of P. vivax is lower in areas where mixed infections are zz In areas with chloroquine-susceptible infections, treat adults and children with uncomplicated P. vivax, P. ovale, P. malariae, common making the diagnosis more difficult. or P. knowlesi malaria (except pregnant women in their first Since the early 1990s RDTs have popularized as trimester) with an ACT. diagnostic tools as they can detect one or more plasmodium Strong recommendation, high-quality evidence

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BOX 2 Preventing relapse in P. vivax or P. ovale malaria References . 1 World Health Organization. (2019). World malaria report 2019. zz To prevent relapse, treat P. vivax or P. ovale malaria in children World Health Organization. Available from https://apps.who.int/ and adults (except pregnant women, infants aged < 6 months, iris/handle/10665/330011 women breastfeeding infants < 6 months, women breastfeeding . 2 World Health Organization. (2018). World malaria report 2018. older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with 14-day course of primaquine World Health Organization. Available from https://apps.who.int/ in all transmission settings. iris/handle/10665/275867 Strong recommendation, high-quality evidence . 3 World Health Organization. (2015). Guidelines for the treatment of malaria, 3rd edition. World Health Organization. Available from zz In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 https://apps.who.int/iris/handle/10665/162441 weeks, with close medical supervision for potential primaquine- . 4 Baird JK. Evidence and implications of mortality associated with induced adverse hematological effects. acute Plasmodium vivax malaria. Clin Microbiol Rev. 2013;26(1): Strong recommendation, high-quality evidence 36-57. . 5 Gething PW, Elyazar IRF, Moyes CL, et al. A long neglected world malaria map: Plasmodium vivax Endemicity in 2010. PLoS Negl Trop In pregnant or breastfeeding women, weekly Dis. 2012;6(9):e1814. . 6 Mendis K, Sina BJ, Marchesini P, et al. The neglected burden of chemoprophylaxis with chloroquine is recommended Plasmodium vivax malaria. Am J Trop Med Hyg. 2001;64(1-2 until delivery followed by completion of breast feeding. Suppl):97-106. Treatment for future replases can then be decided on the 7. Gunalan K, Lo E, Hostetler JB, et al. Role of Plasmodium vivax Duffy- basis of G6PD status (Box 2). binding protein 1 in invasion of Duffy-null Africans. Proc Natl Acad Sci U S A. 2016;113(22):6271-6. 8. Gunalan K, Niangaly A, Thera MA, et al. Plasmodium vivax infections Severe Malaria of Duffy-negative erythrocytes: Historically undetected or a recent All patients including adults, children, infants, pregnant adaptation? Trends Parasitol. 2018;34(5):420-9. women in all trimesters, and lactating women with Severe . 9 World Health Organization. (2014). World malaria report 2014. Malaria are to be treated with intramuscular or intravenous World Health Organization. Available from https://apps.who.int/ iris/handle/10665/144852 artesunate for at least 24 hours and until they are able to 10. Anvikar AR, Shah N, Dhariwal AC, et al. Epidemiology of Plasmodium tolerate oral medication. Artesunate is prescribed at a dose vivax malaria in India. Am J Trop Med Hyg. 2016;95(6 Suppl):108-20. of 2.4 mg/kg at 0, 12, 24, and 48 hours. Once a patient has 11. Naing C, Whittaker MA, Nyunt Wai V, et al. Is Plasmodium vivax received at least 24 hours of parenteral therapy and who malaria a severe malaria?: a systematic review and meta-analysis. can tolerate oral therapy, complete treatment with 3 days PLoS Negl Trop Dis. 2014;8(8):e3071. 12. Patriani D, Arguni E, Kenangalem E, et al. Early and late mortality of an ACT should be advised. Intravenous quinine can after malaria in young children in Papua, Indonesia. BMC Infect Dis. be considered as an alternative agent at a loading dose of 2019;19(1):922. 20 mg/kg followed by 10 mg/kg in 8th hourly dosing only, 13. O’Donnell A, Premawardhena A, Arambepola M, et al. Interaction if artesunate is not available. of malaria with a common form of severe thalassemia in an Asian Symptomatic management of ARDS, seizures, and AKI population. Proc Natl Acad Sci USA. 2009;106(44):18716-21. 14. Dayananda KK, Achur RN, Gowda DC. Epidemiology, drug is to be done according to institutional protocols. resistance, and pathophysiology of Plasmodium vivax malaria. J Vector Borne Dis. 2018;55(1):1-8. Conclusion 15. Imwong M, Snounou G, Pukrittayakamee S, et al. White, relapses of Plasmodium vivax infection usually result from activation of Managing patients with severe malaria should caution the heterologous hypnozoites. J Infect Dis. 2007;195(7):927-33. mind of a clinician in view of Plasmodium vivax as a causative 16. Battle KE, Karhunen MS, Bhatt S, et al. Geographical variation in agent and potential drug resistance in the same. Patient Plasmodium vivax relapse. Malar J. 2014;13(1):144. may present with hemolysis, jaundice, acute renal failure, 17. Anstey NM, Russell B, Yeo TW, et al. The pathophysiology of vivax cerebral malaria, or acute respiratory distress syndrome. Use of malaria. Trends Parasitol. 2009;25(5):220-7. artemesin-based therapy is the treatment of choice for severe 18. Carlton JM, Adams JH, Silva JC, et al. Comparative genomics of and drug resistant malaria caused by Plasmodium vivax. the neglected human malaria parasite Plasmodium vivax. Nature. 2008;455(7214):757-63.

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19. Parroche P, Lauw FN, Goutagny N, et al. Malaria hemozoin is 34. Tjitra E, Anstey NM, Sugiarto P, et al. Multidrug-resistant Plasmodium immunologically inert but radically enhances innate responses by vivax associated with severe and fatal malaria: a prospective study presenting malaria DNA to Toll-like receptor 9. Proc Natl Acad Sci U in Papua, Indonesia. PLoS Med. 2008;5(6):e128. S A. 2007;104(6):1919-24. 35. Barber BE, William T, Grigg MJ, et al. A prospective comparative 20. Andrade BB, Reis-Filho A, Souza-Neto SM, et al. Severe Plasmodium study of knowlesi, falciparum, and vivax malaria in Sabah, Malaysia: vivax malaria exhibits marked inflammatory imbalance. Malar J. high proportion with severe disease from Plasmodium knowlesi 2010;9(1):13. and Plasmodium vivax but no mortality with early referral and 21. Carvalho BO, Lopes SC, Nogueira PA, et al. On the cytoadhesion artesunate therapy [published correction appears in Clin Infect Dis. of Plasmodium vivax-infected erythrocytes. J Infect Dis. 2014;58(4):608]. Clin Infect Dis. 2013;56(3):383-97. 2010;202(4):638-47. 36. Barcus MJ, Basri H, Picarima H, et al. Demographic risk factors for 22. Chotivanich K, Udomsangpetch R, Suwanarusk R, et al. Plasmodium severe and fatal vivax and falciparum malaria among hospital vivax adherence to placental glycosaminoglycans. PLoS One. admissions in northeastern Indonesian Papua. Am J Trop Med Hyg. 2012;7(4):e34509. 2007;77(5):984-91. 23. Udomsangpetch R, Thanikkul K, Pukrittayakamee S, et al. Rosette 37. Bustos MM, Gómez R, Álvarez CA, et al. Adult acute respiratory formation by Plasmodium vivax. Trans R Soc Trop Med Hyg. distress syndrome by Plasmodium vivax. Acta Med Colomb. 1995;89(6):635-7. 2014;39(2):211-5. 24. Totino PR, Lopes SC. Insights into the cytoadherence phenomenon 38. Srivastava S, Ahmad S, Nadia S, et al. Retrospective analysis of of Plasmodium vivax: the putative role of phosphatidylserine. Front vivax malaria patients presenting to tertiary referral centre of Immunol. 2017;8:1148. Uttarakhand. Acta Tropica. 2010;117:82-5. 25. Joy S, Mukhi B, Ghosh SK, et al. Drug resistance genes: pvcrt-o and 39. Kanodia KV, Shah PR, Vanikar AV, et al. Malaria induced acute renal pvmdr-1 polymorphism in patients from malaria endemic South failure: a single center experience. Saudi J Kidney Dis Transpl. Western Coastal Region of India. Malar J. 2018;17(1):40. 2010;21(6):1088-91. 26. Menkin-Smith L, Winders WT. Malaria (Plasmodium vivax) [Updated 40. Silva GBD Junior, Pinto JR, Barros EJG, et al. Kidney involvement in 2019 May 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls malaria: an update. Rev Inst Med Trop Sao Paulo. 2017;59:e53. Publishing; 2020. Available from https://www.ncbi.nlm.nih.gov/ 41. Kimmatkar P, Jhorawat R, Gandhi K, et al. Acute kidney injury in books/NBK538333 patients with Plasmodium vivax malaria: clinicohistopathological 27. Ladeia-Andrade S, Ferreira MU, de Carvalho ME, et al. Age- profile. Saudi J Health Sci. 2016;5:138-41. dependent acquisition of protective immunity to malaria in riverine 42. Bhadauria D, Vardhan H, Kaul A, et al. P. vivax malaria presenting populations of the Amazon Basin of Brazil. Am J Trop Med Hyg. as thrombotic microangiopathy. J Assoc Physicians India. 2009;80(3):452-9. 2017;65(9):28-31. 28. Lin E, Kiniboro B, Gray L, et al. Differential patterns of infection 43. Ozen M, Gungor S, Atambay M, et al. Cerebral malaria owing to and disease with P. falciparum and P. vivax in young Papua New Plasmodium vivax: case report. Ann J Pediatr. 2006;26(2):141-4. Guinean children. PLoS One. 2010;5(2):e9047. 44. Kochar DK, Saxena V, Singh N, et al. Plasmodium vivax malaria. 29. Douglas NM, Anstey NM, Buffet PA, et al. The anaemia of Emerg Infect Dis. 2005;11(1):132-4. Plasmodium vivax malaria. Malar J. 2012;11:135. 45. Gupta P, Das A, Singh OP, et al. Assessing the genetic diversity of 30. Collins WE, Jeffery GM, Roberts JM. A retrospective examination of the vir genes in Indian Plasmodium vivax population. Acta Trop. anemia during infection of humans with Plasmodium vivax. Am J 2012;124(2):133-9. Trop Med Hyg. 2003;68(4):410-2. 46. Gupta P, Pande V, Das A, et al. Genetic polymorphisms in VIR genes 31. Wickramasinghe SN, Looareesuwan S, Nagachinta B, et al. among Indian Plasmodium vivax populations. Korean J Parasitol. Dyserythropoiesis and ineffective erythropoiesis in Plasmodium 2014;52(5):557-64. vivax malaria. Br J Haematol. 1989;72(1):91-9. 47. Mathews SE, Bhagwati MM, Agnihotri V. Clinical spectrum of 32. Wickramasinghe SN, Abdalla SH. Blood and bone marrow changes in Plasmodium vivax infection, from benign to severe malaria: a malaria. Baillieres Best Pract Res Clin Haematol. 2000;13(2):277-99. tertiary care prospective study in adults from Delhi, India. Trop 33. Val F, Machado K, Barbosa L, et al. Respiratory complications of Parasitol. 2019;9(2):88-92. Plasmodium vivax malaria: systematic review and meta-analysis. 48. Ghosh SK, Rahi M. Malaria elimination in India—The way forward. J Am J Trop Med Hyg. 2017;97(3):733-43. Vector Borne Dis. 2019;56(1):32-40.

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Partha S Karmakar

Abstract Majority of emerging and re-emerging diseases are zoonotic. Viral and parasitic infections are more common causative agents for emerging diseases than bacteria. Zoonotic diseases are more likely in our country due to our usual habit of keeping livestock in close proximity. After the last influenza pandemic in 1918, the prevailing COVID-19 pandemic is almost over 1 year in existence. Whole world is now reeling with this emerging infectious disease along with various re-emerging diseases in between.

Introduction „„ New disease „„ Old disease with new feature: Here new means in Since antiquity human population have faced several respect to new location or new population (prevalence epidemics of emerging & re-emerging infectious diseases in different age group), new feature (changed C/F or with a significant death toll. Plague (in 14th century), non-responsiveness to conventional therapy) smallpox (in 16th century) and Spanish flu (in 20th century)—were responsible for huge death to the tune of 200, 56, and 50 millions respectively.1 With the advent Re-emerging Infectious Disease th of antimicrobials and effective vaccines in 20 century A past disease, which was once well controlled or infectious diseases no longer remained the major threat eradicated, has shown its reappearance is considered to 2,3 for mortality, especially in developed countries. But be re-emerging infectious disease. for last few decades a slew of newer infectious diseases (Avian Influenza, NIPAH, SARS, COVID-19) have emerged. Some of them have epidemic potentials with significant Origin of Infectious Diseases morbidity and mortality.4 Majority of EIDs are zoonotic and over 30 new infections have emerged in last three decades globally and most Definitions common agents are viruses & prions (37%) followed by protozoa (26%).5 Many of them have epidemic Emerging Disease or pandemic potentials with high fatality rate and Infectious diseases are said to be EID when incidence ~60% of them are zoonotic in origin, especially wildlife of one Inf. disease has increased abnormally within the in origin.5-7 In India, zoonotic diseases are more likely recent past or threatens to increase in the near future. as livestock usually stay in close proximity to human Diseases that fall in this category are: dwelling.8

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Infections from Animal to Man—How? „„ It could be considered South Asian disease as all the To get into the depth of origin of these EIDs we have to outbreaks (more than ten) after 1999 have occurred in this region only. look back to our changed behavior. Human encroachment to animal habitat through deforestation and use of Human affection: In various ways: terrain for their personal living and farming has lead to „„ More commonly found in male with history of high increased interface with wild animals. This is considered exposure to pigs. to be an important or potential factor for jump of some „„ Food borne by consuming fresh date palm sap microbes (with or without mutation) usually found in contaminated with saliva, urine of fruit bats, natural animal kingdom, to human population. Many of them host of NiV, while they feed on it. have epidemic potential and spread is facilitated across „„ Human to human transmission is possible if patient countries by fast travelling and wild trafficking. has respiratory symptoms.9 Clinical feature: Important Diseases „„ Male predominant disease with M:F = 4.5:1. Important emerging and re-emerging diseases in India in „„ Presents with fever (97%), headache (65%) with altered this millennium that deserve mentioning are: sensorium and abnormal brainstem functions (50%). „„ Dizziness, vomiting, hypotonia, areflexia, Virus: dysautonomia (hypertension, tachycardia, excessive „„ NIPAH (2001)—West Bengal sweating) may be present.10 „„ Chandipura (2003, 2004, 2007)—Andhra Pradesh, „„ Siliguri (West Bengal) cases in 2001 showed additional Gujarat, Maharashtra feature of acute respiratory distress with tachypnea in „„ Chikungunya (2005)—Andhra Pradesh half of the cases, making human to human transmission „„ Influenza-H1N1(2009)—Andhra Pradesh possible (unlike Malaysian outbreak) with high fatality „„ CCHF (2011)—Gujarat of 62.5%.11 „„ COVID-19/SARS-CoV2 „„ NIPAH virus alert in Kerala was again found in 2018. „„ Zika Virus Disease Management and prevention: Bacteria: „„ Mainly supportive and barrier nursing methods are „„ Diptheria (2001–2015)—Many states (Andhra Pradesh, advocated. Assam, Delhi, Gujarat, Karnataka, Nagaland, West „„ Ribavarin—tried but inconclusive in vivo trial. Bengal, etc.) „„ Monoclonal antibody targeting NiV G glycoprotein was „„ Plague (2002, 2004)—Himachal Pradesh, Uttarakhand found to be effective in ferret models. „„ MDR/XDR Tuberculosis „„ Vaccine—a against Hendra virus (used Protozoa: in horses), a member of Henipavirus, offers a great 12 „„ ACT resistant Falciparum Malaria potential for NiV through cross protection.

Chandipura (CHP) Virus Abridged Information of the above Diseases „„ Named as per its first documented place of emergence, are Put Forward Except Malaria and TB Chandipura, Nagpur of India in 1965 and possibly it is sandfly borne disease. Nipah Virus Disease „„ In 2003, Chandipura AES (Acute Encephalitis Nomenclature: Syndrome) outbroke in Children in Andhra Pradesh „„ Nipah virus (NiV) belongs to family Paramyxoviridae & with high fatality (55%) but luckily residual neurological Genus Henipavirus. deficit was rare in recovered children.13 „„ Named according to its first discovery in Sungai Nipah „„ After this two more focal outbreaks were observed in village of Malaysia. Gujarat (2004) and Maharashtra (2007).

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Chikungunya Influenza A Virus caused the largest and the deadliest pandemics before the occurrence of COVID-19 and four Chikungunya is a self limiting disease and prevalent in Influenza A Virus pandemics since beginning of 20th tropical and subtropical areas of Africa and Asia. century: Chikungunya means “to be bent over” as per Swahili „„ Spanish Flu (1918)—due to H1N1 with 50 million death language of Tanzania (Africa) where from the very first „„ Asian Flu (1952)—due to H2N2 case was reported. „„ Hong Kong Flu (1968)—due to H3N2 Causative agent: „„ Mexican Flu (2009)—due to H1N1 pdm09 „„ Chikungunya virus (CHIKV) of arboviridae family of The Mexican Flu (2009) pandemic got spread rapidly the genus alphavirus. to over 214 countries worldwide including India. Globally 15 „„ Vector—day-biting infected Aedes Aegypti and total death toll was 18,449. Albopictus mosquito. A total of 1,54,259 Indians were tested for H1N1 pdm09 „„ Reservoir of infection—Non-human primates influenza till August 8, 2010, with 23.4% being positive including 1,833 reported deaths. Maharashtra and Gujarat Clinical features: were worst affected states.16 „„ High fever (102–05°F) with severe joint pain (patient becomes bent over) and skin rash. Treatment: „„ Usually follow acute self limiting course but around „„ Supportive therapy 10–15% of cases develop subacute (3 weeks to 3 „„ Neuraminidase inhibitors—Block virus release from months), or chronic Chikungunya. infected cells. Used both for prophylaxis & therapy: „„ Chronic Chikungunya may present as RA or post- —— Oseltamivir—Oral Formulations for use. chikengunya-rheumatic muskuloskletal (pcRMSK) —— Zanamivir—IV Last two molecules are — disorder. — Peramivir—IV/IM unavailable here. After 1973, in 2006 re-emergence of chikungunya —— Laninamivir—Intranasal infection in India was found in epidemic form and affected 1.2 million Indians with high morbidity rate.14 From 2006 Crimean-Congo Hemorrhagic Fever (CCHF) to 2012 chikungunya was reported from 22 States and Name was derived from the first two places of its union territories. occurrence—Crimea (in 1944) & Congo (in 1956) caused Diagnostic test: by single stranded RNA virus of Bunyaviridae family. „„ IgM against CHIKV Virus continues its life by animal (livestock)-tick- animal cycle. Treatment: Human gets infection by: „„ NSAID for 1 or 2 weeks will suffice in majority of „„ Infected tick bites patients. „„ Handling of infected animal tissues (Slaughter house „„ Chronic cases may need anti-rheumatic drugs like workers, farmers, veterinarians) hydroxychloroquine or methotrexate. Clinical feature: „„ Incubation period 1–9 days. Influenza Virus (H1N1) „„ High index of clinical suspicion is needed. Presents Influenza virus is a respiratory virus and is of 4 types—A, with fever, myalgia, headache, lymphadenopathy, and B, C, and D. bleeding manifestation (varying from petechial rash to Type A Influenza Viruses has produced several internal mucosal bleeding).17 pandemics in humans and is nomenclatured depending „„ Fatality rate ranges from 9% to 50%. on which one of 18 different Hemagglutinins (HA) & India saw the confirmed outbreak of CCHF in 2011 in 11 different Neuraminidases (NA) is present as surface Gujarat.18 Total 42 cases were reported till 2013 with high protein. It originates either as Avian or Swine. death rate of 59.9%.

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Important D/Ds: fatality of unknown etiology was noticed, later proved to DHF, leptospirosis, severe malaria, meningococcal be caused by novel corona virus (SARS-CoV-2/COVID-19) infection, and other viral hemorrhagic fevers. with human to human transmission. Origin of Novel CoV Infection—Speculated to have Diagnosis: originated from bats, a natural carrier of CoV, but bats „„ RT-PCR—sensitive, specific remain in hibernation during winter. As low temperature „„ Rapid test prevails in December in China, so intermediate host „„ Antibody—antiviral IgG and IgM detection was thought of. The virus likely jumped to humans from Treatment: pangolins (long snouted mammals often used in food and „„ Supportive therapy traditional Chinese medicine) along with possibly other „„ Ribavirine—if instituted within 5 days possibly multiple intermediate hosts. improves the prognosis Burden of COVID-19 patients—Infection rate of COVID-19 per day is varying greatly from country to country. Many COVID-19/SARS-CoV2 western countries are braced with 2nd wave of COVID. Microbes in their quest to be ahead of human, they Highest infection in a day in India till 20/12/2020 was undergo some mutation to increase their capability of found on 11/09/2020 and it was 97,570. Little short of jumping to human from their animal source and human to 1 lakh/day. Gradually with some fluctuation it then came human transmission as well to reach epidemic/pandemic down to 26,624 on 19/12/2020. Total burden of COVID as potential. While this article is being written whole world on 20/12/2020 is shown in Table 1. is reeling under the threat of a zoonosis COVID-19/SARS- Vaccines update (till December, 2020)—Researchers CoV2—biggest threat in last 100 years. throughout the world putting in great efforts round the Corona Virus-related Diseases clock to contain the devastating situation of COVID-19 pandemicity by finding an effective treatment and/ Corona virus (CoV), a respiratory virus, normally causes or vaccine against SARS-CoV2. This has lead to an diseases in mammals (including birds) like—camels, unprecedented public/private partnership to go through a civets, bats, etc. This virus is transmitted to human fast tracked vaccine development process. through droplet/fomite & usually produces mild-to- On August 11, 2020, Russia make COVID vaccine, moderate respiratory illness. But through mutation it has Sputnik-V, is the world’s first vaccine as per bulletin of caused following diseases with high fatality rate: Ministry of Health of Russian Federation. Russia has „„ Severe Acute Respiratory Syndrome (SARS)—First started Phase 3 and Phase 4 (administration to general noticed in 2002 in China, soon followed by worldwide people) trial simultaneously though experts has raised spread with total reported 8,000 cases and 800 deaths. their concern for safety profile (Table 2). It was acquired from bat.19 India too is progressing fast keeping pace with other „„ Middle East respiratory syndrome (MERS)—Acquired countries. As per ICMR reporting on 20th August, 2020, from dromedary camels (affected from bat). First two indigenously developed vaccine candidates—Bharat noticed in 2012 in Saudi Arabia then spreading to other Biotech’s COVAXIN (both intrademal & IM), Zydus Arabian Peninsula and Republic of Korea. By 2016, Cadilla’s Zycov-D have started human trial in India, so over 1,700 cases detected with mortality of 35%. also Oxford Astra-Zeneca’s Covidsheild with its Pune based „„ Novel Corona Virus Disease (COVID-19/SARS- CoV2)—This ongoing pandemic is being greatest threat of all infectious diseases in last hundred years. Discussed below briefly. TABLE 1 Burden of COVID (on 20/12/2020)

COVID-19/SARS-CoV2 Disease Scenario Total COVID-19 cases Recovered cases Deceased Global 7,66,26,187 5,37,51,202 16,91,942 In December 2019 in Wuhan, Hubei Province of China, an epidemic of respiratory illness with moderately high India 1,00,47,131 95,95,711 1,45,669

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TABLE 2 Few more vaccines globally underway

Candidate Sponsor Trial phase Institution bacTRL-Spike Symvivo Pre-clinical Symvivo Corporation PittCoVacc UPMC/University of Pittsburgh School of Medicine Pre-clinical University of Pittsburgh Recombinant vaccine Vaxart Pre-clinical Vaxart

manufacturing partner Serum Institute of India. Oxford- Silent Hypoxia in COVID AstraZeneca vaccine may be the first shot available for Silent hypoxia is a danger sign of COVID-19 infection. Indians by the end of 2020. It means person’s oxygen level in blood cells and tissue AstraZeneca is likely to get regulatory approval from may drop due to COVID-related diffuse pneumonia the UK’s independent regulator by the end of this year for without any initial warning in the form of cough, dyspnea, a rollout to begin in early 2021, according to the UK Oxford tachypnea, etc. until patient develops ARDS. University/AstraZeneca vaccine company. So arterial O saturation (SpO ) detection at regular Trials of the Oxford vaccine show the following as per 2 2 their claim: intervals is a must for detection of silent hypoxia and to initiate supportive therapy at earliest possibility. „„ Stop 70% of people developing Covid symptoms. Could increase protection up to 90% „„ The data also shows a strong immune response in older Treatment people No full-poof definitive but supportive therapy available at „„ It is given in two doses present. „„ Trials with more than 20,000 volunteers are still Aggressive isolation measures aimed at reducing continuing transmission in the community is our best weapon. This may be one of the easiest vaccines to distribute, because it does not need to be stored at very cold The followings had been tried with mixed results: temperature. „„ Hydroxychloroquine (HCQ): Antimalarial with in- It is made from a weakened version of a common cold vitro activity against SARS-CoV-2 and may have virus from chimpanzees that has been modified to not immunomodulating properties. WHO recommends grow in humans. for prophylaxis but not for therapy (directive on WHO and most nations globally are willing to prioritize 25/05/2020). vaccine recipients as follows: „„ Azithromycin: Shows anti-SARS-CoV-2 activity in vitro. „„ Health-care workers (HCW) „„ Anti-influenza agent (Favipiravir, Oseltamivir) and „„ People >65 years of age broad-spectrum antiviral (Remdesivir), anti-HIV agent „„ People with comorbidities (like DM, Cancers, CVD, (Lopinavir/Rtonavir): Showing varying degree of COPD) activity against corona viruses in vitro. Clinical feature: „„ Convalescent plasma: Tried in severe or immediately „„ Incubation period—2–14 days life-threatening COVID-19 infections with favorable „„ Asymptomatic—some patients result in some studies. „„ Majority shows features of fever (45.4%), headache „„ HFNO (High flow nasal oxygen): HFNO in awake prone (70.3%), dry cough (63.2%), sore throat (52.9%), position is considered to be win-win position to avoid

asthenia (63.3%), and some developed dyspnea. invasive ventilator in some patients of declining SpO2. Anosmia (70.2%) and altered taste sensation (49.8%) „„ Other therapies: Anticoagulant (LMWH), Anti IL6 may be early symptoms in some patients.20 receptor inhibitor (Tocilizumab), Invasive Ventilator, „„ Diarrhea may be the presenting feature of COVID-19 in ECMO (extra-corporeal membrane oxygenation) are ~20% of cases. other therapeutic options in some specific patients.

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Case fatality: Differs in different countries. In India, till may lead to waning immunity against diphtheria among August 2020 overall mortality was ~1.56. school-going children and adults.24 Some Indian study showed higher prevalence among muslim children and it Mortality increases significantly in: was about 38% in Delhi as stated in a study.24 „„ Patients >65 years „„ Patients with comorbidities (DM, renal failure, COPD, on chemotherapy, etc.) Plague „„ Patients needing ventilatory support We doctors now bear a wrong impression that plague is almost nonexistent in India and not getting proper Zika Virus emphasis in medical undergraduate and postgraduate Zika virus disease is caused by the Flavivirus, the same teaching. So doctors are not properly aware of its family of virus causing dengue. Several Zika virus outbreaks consideration in differential diagnoses. were found in both North & South America since 2015, but Plague infection in India continues to exist as enzootic it has emerged in India just with only three (3) confirmed in wild rodents and epizootic spread of plague from wild cases in 2017—as per report of Ministry of Health & Family to commensal rodents facilitate human transmission. Welfare, Govt. of India. All these three cases were reported Thus, it leads to re-emergence/outbreaks of plague in from Bapunagar, Gujarat. India in 2002 (Shimla, HP) and 2004 (Uttarakhand) of this 25,26 „„ Transmission: millennium. —— Mainly by bite of infected Aedes mosquito. —— Sexual activity and blood transfusion can Causative Agent and Transmission in Humans sometimes lead to this disease transmission.21 Plague is a zoonoses (wild rodents) and caused by Gram- „„ Clinical features: Majority (80%) are asymptomatic, negative bacilli, Yersinia pestis, spreading between rodents 20% of cases have low grade fever, myalgia, rash, and through their fleas. sore throat. Ways of transmission to man: „„ Concern lies if pregnant women contract this disease „„ By bite of infected fleas in first trimester, which may lead to microcephaly and „„ Coming in contact with infected tissues of rodent brain abnormalities of infant.22 „„ Human to human transmission through droplets in pneumonic plague Diphtheria We all know that exotoxin-producing Corynebacterium Conclusion diphtheria is the causative agent. Its incidence has reduced This has been proved beyond doubt that significant percentage to a great extent globally due to successful implementation of infectious diseases are zoonotic in origin. In last three of childhood vaccination. From 1 million before 1980s decades thirty (30) emerging infectious diseases detected to 1 lakh in 1980 and reduced to 4.5 thousand in 2015. globally, majority of them are viral in origin and approximately Diphtheria is a rare disease in developed countries but 60% of them are zoonotic especially wildlife in origin. In India global burden contributed mainly by sub-Saharan Africa, zoonotic diseases are more likely as here domestic/pet animals 23 India, and Indonesia. are kept in close proximity to their residence. In 15 years tenure (during 2001–2015) almost half of Through awareness and/or legislation if we can make the global diphtheria cases were from India, and CBHI human contact with animals (domestic/wild) scientifically (Central Bureau of Health Intelligence) India reported modified or restricted (in some situations) emerging and re- 41,672 cases of Diphtheria in 10 years (2005–2014) with emerging diseases could be avoided globally to a great extent. mortality of 2.2% cases. Diphtheria is now considered EID as it shifts toward References higher median age than its earlier preference for under 1. Nicholas LePan, Visualizing the History of Pandemics. Available from five children. It could be related to lack of 100% coverage of https://www.visualcapitalist.com/history-of-pandemics-deadliest/ three doses of diphtheria vaccination (80% coverage) and 2. Hopkins DR. Princes and peasants smallpox in history. In: Hopkins expected low coverage of booster dose after 10 years. This DR (Ed). Chicago IL: University Chicago Press; 1983. pp. 204-33.

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